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Editors: Basic and Preclinical Research: Drug Development: Early Breast Cancer: Advanced Breast Cancer: Gastrointestinal Cancers: Genitourinary Cancers: Lung Cancer: Gynaecological Cancers: Head and Neck Cancer: Sarcomas: Melanoma: Neuro-oncology: Epidemiology and Prevention: Paediatric Oncology: Founding Editor: Past Editors: Editorial Office:

Alexander M.M. Eggermont Institut Gustave Roussy Villejuif, France Richard Marais, Manchester, UK Giorgio Parmiani, Milan, Italy Jean-Charles Soria, Villejuif, France Kathleen I. Pritchard, Toronto, Canada David Cameron, Edinburgh, UK Eric Van Cutsem, Leuven, Belgium Michel Ducreux, Villejuif, France Cora Sternberg, Rome, Italy Mary O’Brien, London, UK Ignace Vergote, Leuven, Belgium Kevin Harrington, London, UK Jean-Yves Blay, Lyon, France Dirk Schadendorf, Essen, Germany Roger Stupp, Zurich, Switzerland Jan Willem Coebergh, Rotterdam, The Netherlands Rob Pieters, Rotterdam, The Netherlands Henri Tagnon Michael Peckham, London, UK; Hans-Jo¨rg Senn, St Gallen, Switzerland; John Smyth, Edinburgh, UK Elsevier, The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Tel: +44 (0) 1865 843590, Email: [email protected]

EDITORIAL BOARD CLINICAL ONCOLOGY J.-P. Armand (France) A. Ayhan (Japan) R. Blamey (UK) M. Bolla (France) J. Boyages (Australia) N. Bru¨nner (Denmark) F. Cardoso (Portugal) J. Cassidy (UK) M. Castiglione (Switzerland) L. Cataliotti (Italy) L. Cheng (USA) H. Cody (USA) R. Coleman (UK) A. Costa (Italy) J. De Bono (UK) M.J.A. De Jong (The Netherlands) E. de Vries (The Netherlands) A. Dicker (USA) R. Dummer (Switzerland) F. Eisinger (France) S. Erridge (UK)

G. Ferrandina (Italy) H. Gabra (UK) H. Gelderblom (The Netherlands) B. Hasan (Belgium) J.C. Horiot (Switzerland) C. Huber (Germany) R. Jakesz (Austria) J. Jassem (Poland) D. Jodrell (UK) V.C. Jordan (USA) A. Katz (Brazil) M. Kaufmann (Germany) I. Kunkler (UK) L. Lindner (Germany) P.E. Lønning (Norway) P. Lorigan (UK) K. McDonald (Australia) R. Mertelsmann (UK) F. Meunier (Belgium) T. Mok (Hong Kong) D. Nam (Korea)

P. O’Dwyer (USA) J. Overgaard (Denmark) N. Pavlidis (Greece) J. Perry (Canada) P. Price (UK) D. Raghavan (USA) J. Ringash (Canada) J. Robert (France) A. Rody (Germany) D. Sargent (USA) M. Schmidinger (Austria) S. Sleijfer (The Netherlands) P. Sonneveld (The Netherlands) A. Sparreboom (USA) M. van den Bent (The Netherlands) M. Van Glabbeke (Belgium) G. Velikova (UK) U. Veronesi (Italy) A. Vincent-Salomon (France) A. Voogd (The Netherlands) E. Winquist (Canada)

BASIC, PRECLINICAL AND TRANSLATIONAL RESEARCH A. Albini (Italy) P. Allavena (Italy) F. Balkwill (UK) M. Barbacid (Spain) M. Broggini (Italy) C. Catapano (Switzerland) J. Collard (The Netherlands) E. Garattini (Italy)

A. Gescher (UK) R. Giavazzi (Italy) I. Hart (UK) W. Keith (UK) L.A. Kiemeney (The Netherlands) J. Lunec (UK) D.R. Newell (UK) G.J. Peters (The Netherlands)

A. Puisieux (France) V. Rotter (Israel) M. Schmitt (Germany) C.G.J. Sweep (The Netherlands) G. Taraboletti (Italy) P. Vineis (UK) N. Zaffaroni (Italy)

A. Green (Australia) K. Hemminki (Germany) C. Johansen (Denmark) L.A. Kiemeney (The Netherlands) M. Maynadie´ (France) H. Møller (UK) P. Peeters (The Netherlands)

S. Sanjose (Spain) M.K. Schmidt (The Netherlands) H. Storm (Denmark) L.V. van de Poll-Franse (The Netherlands) H.M. Verkooijen (The Netherlands) R. Zanetti (Italy)

G. Chantada (Argentina) F. Doz (France) A. Ferrari (Italy) M.A. Grootenhuis (The Netherlands) K. Pritchard-Jones (UK)

L. Sung (Canada) M. van den Heuvel-Eibrink (The Netherlands) M. van Noesel (The Netherlands)

EPIDEMIOLOGY AND PREVENTION B. Armstrong (Australia) P. Autier (France) J.M. Borras (Spain) C. Bosetti (Italy) J. Faivre (France) S. Franceschi (France) D. Forman (France)

PAEDIATRIC ONCOLOGY C. Bergeron (France) A. Biondi (Italy) E. Bouffet (Canada) M. Cairo (USA) H. Caron (The Netherlands)

EJC Supplements Aims and Scope EJC Supplements is an open access companion journal to the European Journal of Cancer. As an open access journal, all published articles are subject to an Article Publication Fee. Immediately upon publication, all articles in EJC Supplements are made openly available through the journal’s websites. EJC Supplements will consider for publication the proceedings of scientific symposia, commissioned thematic issues, and collections of invited articles on preclinical and basic cancer research, translational oncology, clinical oncology and cancer epidemiology and prevention. Authors considering the publication of a supplement in EJC Supplements are requested to contact the Editorial Office of the EJC to discuss their proposal with the Editor-in-Chief. 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Vol. 11 Number 2 September 2013 ISSN 1359-6349

EJC Supplements Education Book

European Cancer Congress, Amsterdam 27 September – 1 October 2013 Scientific Editor: Professor Irving Taylor

Disclaimer All advertising material in this publication is expected to conform to ethical (medical) standards, and does not constitute a guarantee or endorsement of the quality or value of such product or the claims made of it by its manufacturer, and is intended for prescribing healthcare professionals only. No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.

Amsterdam • Boston • London • New York • Oxford • Paris • Philadelphia • San Diego • St Louis

The 2013 European Multidiciplinary Cancer Congress Educational Programme Table of Contents Editorial

vi

Educational Symposia Saturday, 28 September 2013 – Optimal Approach in Early Breast Cancer Introduction The optimal approach to early breast cancer Optimal approach in early breast cancer: Adjuvant and neoadjuvant treatment The role of the pathologist in the decision-making process Optimal approach in early breast cancer: Radiation therapy

1 3 23 27

Saturday, 28 September 2013 – Optimal Approaches for Localised Rectal Cancer Introduction Optimal approach for localised rectal cancer Optimal imaging staging of rectal cancer Neoadjuvant therapy before surgical treatment The modern anatomical surgical approach to localised rectal cancer Adjuvant chemotherapy

37 38 45 60 72

Sunday, 29 September 2013 – Optimal Approach for Melanoma Introduction Optimal approach for melanoma Melanoma epidemiology, biology and prognosis Targeted therapy in melanoma – the role of BRAF, RAS and KIT mutations Immunotherapy of melanoma Adjuvant therapy for high-risk melanoma

80 81 92 97 106

Monday, 30 September 2013 – Optimal Approach for Upfront Resectable NSCLC Introduction Optimal approach for upfront resectable non-small-cell lung cancer Surgical treatment of early-stage non-small-cell lung cancer Role of adjuvant radiotherapy in completely resected non-small-cell lung cancer Adjuvant chemotherapy of non-small-cell lung cancer Prognostic factors in resected lung carcinomas The seventh tumour–node–metastasis staging system for lung cancer: Sequel or prequel?

109 110 123 131 137 150

Monday, 30 September 2013 – Optimal Approach for Renal Cancer Introduction Optimal approach for renal cancer Individualising treatment choices in a crowded treatment algorithm Does a reasonable treatment approach beyond second-line exist? Understanding and managing toxicities of vascular endothelial growth factor (VEGF) inhibitors Integrating metastasectomy and stereotactic radiosurgery in the treatment of metastatic renal cell carcinoma

159 160 169 172 192

Monday, 30 September 2013 – Mood Disorders in Cancer Patients Introduction Mood disorders in cancer patients Depression in cancer patients Anxiety and sleep disorders in cancer patients Chemotherapy-related changes in cognitive functioning Drug-associated delirium in cancer patients

204 205 216 225 233

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Contents

v

Tuesday, 1 October 2013 – Lung Cancer in Non-smokers Introduction Lung cancer in non-smokers Prevention – Passive smoking and pregnancy Molecular profile of lung cancer in never smokers

241 242 248

Teaching Lectures Saturday, 28 September 2013 Bone metastases: Causes, consequences and therapeutic opportunities Bone-targeted therapy in prostate cancer Current role of human papillomavirus in head and neck oncology Novel therapeutic targets in diffuse large B-cell lymphoma Novel treatment options in early-stage non-small-cell lung cancer Oncoplastic surgery – Standard of care Role of aggressive surgery for peritoneal metastases Successful clinical translation of preclinical combinations of radiation and immunotherapy

254 257 260 262 264 266 268 270

Sunday, 29 September 2013 At what price do we treat patients with testicular cancer? Collaborative international oncology nursing research is improving but still has a long way to go! Experiences, possibilities and challenges Epidermal growth factor receptor targeting and its role for individualisation in radiation oncology From novel insights in molecular biology to targeted treatment approaches in head and neck cancer Metastatic melanoma: New paradigms of treatment and new toxicities Pharmacogenetics in the clinic Radiotherapy for rectal cancer: Short course versus long course – When and how State of the art in neoadjuvant therapy of breast cancer Surgical management of neuroendocrine tumour (NET) liver metastases

271 273 274 275 278 281 282 284 286

Monday, 30 September 2013 Application of sentinel nodes in gynaecological cancer therapy Best management of locally advanced inoperable breast cancer Cancer invasion and resistance Nurse navigation is helpful for cancer patients, but with some restrictions Nutritional status in relation to treatment modalities The best treatment for older patients with breast cancer

287 289 291 294 296 299

Tuesday, 1 October 2013 Mechanisms of treatment-related symptoms in cancer patients Modern management of penile cancer Practical tips and tricks with recently approved molecular targeted agents in non-small-cell lung cancer Role of expert centres in the management of sarcomas Therapeutic procedures in liver metastases: Conventional and future measures Together we are better: Establishing a community oncology nursing programme to improve cancer care through shared working

301 303 307 310 312 314

Editorial

2013 European Multidisciplinary Cancer Congress Education Book Irving Taylor

1.

Introduction

It is my pleasure to present, on behalf of the European Cancer Organisation, the education book for the 2013 European Multidisciplinary Cancer Conference. The comprehensive educational programme for the conference has been developed as a result of the collaborative work of both the scientific and educational committees of ECCO. Readers will note that the book covers a number of important topics relating to common solid malignancies with the overall theme of achieving an optimal approach and therefore optimal results for our patients. The topics covered are localised rectal cancer, early breast cancer, resectable non-small-cell lung cancer, renal cancer and melanoma. We have also included an extremely important section on the mood disorders in cancer patients. In each chapter relating to specific solid tumours, an approach to achieving optimal outcomes is discussed by a consideration of the basic biological characteristics of the tumour and its clinical management, as well as the integration of the two. It is remarkable how similar the basic principles of management for each of the tumours are. For example, the importance of careful preoperative staging with modern imaging and good, careful and fastidious surgical resection is crucial and strongly emphasised. For this to be achieved, specialised understanding of the biology of the tumour and its anatomical confines is essential. Accordingly surgical specialisation is now a mandatory requisite since outcome correlates with volume of patients treated.

The importance of a careful pathological examination is emphasised, not only to determine prognosis but also to determine the most effective adjuvant and in some cases, neoadjuvant treatment that is required. There is increasing emphasis on personalised treatment determined by biological variables, and this is also emphasised in each chapter. In addition, the morbidity and indeed mortality associated with the specific modalities of treatment are documented so that risk–benefit analyses can be assessed. As clinicians, we must not ignore the importance of economic consequences and resource implications of treatments, and this societal concern is also discussed. Finally, the importance of an integrated multidisciplinary approach to the management of these tumours is emphasised by all authors. The authors of each chapter are to be congratulated for providing excellent up-to-date reviews backed by detailed and comprehensive lists of key references which include all the major randomised clinical trials and meta-analyses for the particular malignancy. Readers will find this particularly useful in determining their decision-making. I would like to thank all our authors and Chairs for their hard work in providing chapters for this educational book, and I hope our readers find their efforts worthwhile. I am particularly grateful to Samira Essiaf for her invaluable expertise in preparing the book and dealing with all the administration. I do hope you find the chapters helpful and of educational benefit and enjoy reading them as much as I enjoyed editing them.

1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.064

Introduction

The optimal approach to early breast cancer Lynda Wyld

*

University of Sheffield, Academic Unit of Surgical Oncology, Royal Hallamshire Hospital, UK

Breast cancer outcomes continue to improve, with 5-year survival rates having increased from 50% in the 1970s to nearly 80% today. The reasons for the improvement are multifactorial, with major contributions made by the advent of screening and improved systemic therapies such as anti-oestrogens, chemotherapy and trastuzumab. Running alongside this improvement in breast-cancer-specific survival has been an increasing realisation that preservation of the breast, without compromise on rates of local control, is important for quality of life. This has led to progress in techniques of breast reconstruction and breast conservation, with oncoplastic techniques to reshape the breast, minimising distortion and asymmetry and increasing the use of primary systemic therapy to enhance rates of conservation. Whilst surgery to the breast itself is becoming more complex, surgery to the axilla is becoming less extensive as there is an increasing realisation that the main value of identifying axillary disease is not to enhance survival, or even local control, but to give prognostic information to guide adjuvant therapies. This drive has seen a move away from axillary clearance to sentinel-node biopsy, and perhaps eventually only axillary imaging assessment, with the development of increasingly sensitive tests such as magnetic resonance imaging (MRI) and positron emission tomography (PET) [1]. The changes to practice have been driven by research evidence, and the overarching theme is that of individualised therapy. This is true of all the disciplines in the breast care team. Surgery is now tailored to the woman’s disease, breast shape and size and personal preferences, and in most cases women may be offered surgery that will retain, restore or even enhance her breasts should she so wish. Radiotherapy is increasingly targeted to maximise the dose to the breast whilst reducing the dose to the surrounding tissues using highly complex computed-tomography-guided planning (tomotherapy and intensity-modulated radiation therapy, IMRT). Perhaps the most complex area of all is the interplay

between the molecular pathology of the tumour and the systemic therapy which is offered. Tumour stage, grade and oestrogen receptor status have now been supplemented with Her2 status, and increasingly the proliferation index, Ki67, resulting in a new classification (luminal A, B, Her2+ and basal-like) [2] which guides prognosis and predicts treatment response. More detailed recurrence risk assessments may be provided by multigene arrays such as Oncotype DxTM (Genomic Health, United States of America (USA)) [3] and MammaPrintTM (Agendia BV, The Netherlands) [4] which may further aid decisions about chemotherapy benefits. The future for breast cancer treatment will hold even more individualised treatment plans than the complex schedules on offer today. Next-generation sequencing opens up the possibilities for identification of even more complex gene signatures [5], which may permit customised therapies with some of the bewildering array of targeted molecular therapies under development. Increasing rates of complete pathological responses to primary systemic therapy may lead to ‘no surgery’ options: something which is currently being trialled in respect of both the axilla and the breast. Central to all of the above is the close working relationship of the breast multidisciplinary team. Each must have not only expertise in their own discipline but awareness of what their colleagues can (and cannot) achieve, so that every patient receives an individualised treatment plan that fits together like a perfect jigsaw, with every piece complementing the others. The following articles have been written by some of the world leaders in the field of breast care, and exemplify these principles of individualised care and multidisciplinarity.

Conflict of interest statement None declared.

* Tel.: +44 114 2268640. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.026

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R E F E R E N C E S

[1] Cooper KL, Meng Y, Harnan S, et al. Positron emission tomography (PET) and magnetic resonance imaging (MRI) for the assessment of axillary lymph node metastases in early breast cancer: systematic review and economic evaluation. Health Technol Assess 2011;15:1–134. [2] Perou CM, Parker JS, Prat A, Ellis MJ, Bernard PS. Clinical implementation of the intrinsic subtypes of breast cancer. Lancet Oncol 2010;11:718–9 [author reply 20–1].

11 ( 2 01 3 ) 1–2

[3] Paik S, Tang G, Shak S. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006;24:3726–34. [4] van‘t Veer L, Dai H, van de Vijver Mea. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:530–6. [5] Russnes HG, Navin N, Hicks J, Borresen-Dale AL. Insight into the heterogeneity of breast cancer through next-generation sequencing. J Clin Invest 2011;121:3810–8.

Optimal approach in early breast cancer: Adjuvant and neoadjuvant treatment J. Ribeiro, B. Sousa, F. Cardoso

*

Champalimaud Cancer Center, Breast Unit, Lisbon, Portugal

1.

Introduction

assess the practical contribution of gene expression profiling in breast cancer.

The treatment of early breast cancer (EBC) is becoming increasingly complex, but also more effective as a better understanding of cancer biology is achieved with evolving research. Longer follow-up of prospective trials is crucial to evaluate the impact of current standard treatments in longterm outcome and safety. In this review we will summarise the current evidence for optimal treatment of EBC.

2. Which EBC patients adjuvant chemotherapy?

can

safely

avoid

In the 1980s there were substantial advances in the treatment of breast cancer (BC), and the results of several large randomised trials indicated that adjuvant systemic therapy could decrease breast-cancer mortality by about 20%. In fact, the widespread application of adjuvant systemic therapy is considered the main cause for the declining breast cancer mortality observed in the Western world. Treatment decisions are based on clinical (biological age, comorbidities, performance status) and pathological variables – tumour size, lymph-node status, histological grade, oestrogen receptor (ER), progesterone receptor (PR), HER2 and proliferation – that can be combined in the form of algorithms (e.g. Adjuvant!Online, Nottingham prognostic index) and form the basis of treatment for guidelines such as the ones from the European Society for Medical Oncology (ESMO), the National Comprehensive Cancer Network (NCCN), and St Gallen. However, it is clear that still too many patients receive this therapy with little likelihood of benefit and substantial toxicity. In this section, available data on biomarkers and molecular tests related to prognostication will be reviewed. In the first part we will address the evidence and utility for adjuvant treatment decisions of biomarkers of proliferation (namely Ki67) and urokinase plasminogen activator (uPA)/plasminogen activator inhibitor (PAI-1). In the second part we will

2.1.

Biomarkers

2.1.1.

Markers of proliferation – Ki67

Uncontrolled proliferation is a driver for cancer and is one of the hallmarks of this disease. In general, markers of an elevated proliferative rate correlate with a worse prognosis in untreated patients and may add predictive information regarding benefit from chemotherapy (CT) [1]. The most commonly used method to measure proliferation involves immunohistochemical (IHC) detection of the nuclear non-histone protein ki67, which is detected only in proliferating cells. Ki67 expression is commonly assessed using the mindbomb E3 ubiquitin protein ligase 1 antibody (MIB1) and reported as a percentage of cells positive for Ki67.

2.1.2.

Prognostic marker

Various studies have investigated the role of Ki67 as a prognostic marker. In a meta-analysis of 40 studies, involving over 11,000 patients, baseline Ki67 was found to have a modest prognostic value in multivariable analysis, which was more evident in lymph-node-negative patients [2]. In another meta-analysis of 46 studies including over 12,000 patients, Ki67 positivity (using cut-offs defined by individual authors) was associated with a higher risk of relapse and a worse survival in patients with EBC [3]. One must highlight several limitations of these data: namely the facts that these are retrospective studies, many include heterogeneous groups of patients who were treated and followed in various ways that are often incompletely documented, and ki67 methodology and cutoff varied widely. The clinical utility of Ki67 as a prognostic marker is more apparent when it is considered within more narrowly defined tumour subgroups and/or as part of a multiparameter panel of biomarkers, as for example in the IHC4 [4]. Other investigators have reported that Ki67 is an important part of a prognostic

* Corresponding author: Address: Breast Unit, Champalimaud Cancer Center, Av. De Brası´lia – Doca de Pedrouc¸os, 1400-048 Lisbon, Portugal. Tel.: +351 (210) 480 004; fax: +351 (210) 480 298. E-mail address: [email protected] (F. Cardoso). 1359-6349/$ - see front matter Copyright  2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.029

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algorithm for residual risk in EBC patients treated with letrozole or tamoxifen [5].

2.1.3.

Predictive marker

Studies have focused on the predictive value of this biomarker regarding benefit from CT or even from specific CT agents. In the ER-positive BC the results are contradictory. In the recently reported PACS 001 and BCIRG 001, high levels of Ki67 were predictive of benefit from adding docetaxel to fluorouracil, epirubicin and cyclophosphamide (FEC) CT as adjuvant treatment [6]. However, these results contrast with those from the International Breast Cancer Study Group Trials (IBCSG) VIII and IX that found no predictive value of Ki67 levels for the addition of cyclophosphamide, methotrexate and fluorouracil (CMF) to endocrine therapy (ET) in endocrineresponsive node-negative disease [7]. For ER-negative BC data to suggest that Ki67 predicts adjuvant chemotherapy response are scarce. However, taking into account all the available evidence that these tumours as a group are more responsive to chemotherapy than ER-positive tumours [8,9], one can hypothesise that higher chemotherapy sensitivity observed in patients with ER-negative tumuors is at least partially due to the consistently higher rates of proliferation of these tumours. If so, Ki67 levels may be helpful in identifying those patients most likely to benefit from chemotherapy [10]. In spite of consistent data on Ki67 as a prognostic marker in early breast cancer, its role in breast cancer management remains uncertain [11], mainly because of the lack of standardisation. In 2007 the ASCO Tumour Marker Guidelines stated that evidence supporting the clinical utility of Ki67 was insufficient to recommend its routine use for prognostic purposes in patients with newly diagnosed breast cancer [12]. However, in the St Gallen Consensus guidelines from 2011 [13] and 2013 most panelists recommend the use of Ki67 for BC subtyping classification, prognostication and prediction of response to CT, although there is no consensus on the best cut-off to be used. The limitations of this assay are largely related to the difficulty in interpreting the literature due to lack of standardisation of assay reagents, procedures and scoring. To overcome these constraints in 2011 the International Ki67 in Breast Cancer Working Group published recommendations for Ki67 assessment in breast cancer [14]. These guidelines aim to minimise pre-analytical and analytical variables in Ki67 assessment and harmonise scoring methodology and data handling, facilitating its routine use in clinical practice.

2.1.4. Urokinase activator inhibitor

plasminogen

activator/plasminogen

uPA and PAI-1 biomarkers are invasion biomarkers analysed by a protein-based enzyme-linked immunosorbent assay (ELISA). They can be used to determine the recurrence risk in patients with node-negative EBC with the aim of better refining the decision to recommend CT in this patient population. uPA is a serine protease with an important role in cancer invasion and metastases [15]. When bound to its receptor (uPAR), uPA converts plasminogen into plasmin and mediates degradation of the ECM during tumour-cell invasion. PAI-1 levels are high in tumour tissue and plasma, and PAI-1 is inactivated when bound to uPA.

1 1 ( 2 0 1 3 ) 3 –2 2

Several retrospective studies [16,17] and a large pooled analysis of individual patient data from 8377 women treated in clinical trials by the European Organisation for the Research and Treatment of Cancer (EORTC) [18], in which tumour uPA and PAI-1 levels were determined in primary tumour tissue extracts, proved that high levels of uPA, uPAR, and PAI-1 are associated with shorter survival in women with both node-negative and node-positive disease. The Chemo N0 is a prospective, multicentre randomised trial in which researchers stratified patients with node-negative BC into two groups according to the presence of low or high uPA/PAI-1 values. Those with low values of both uPA and PAI-1 received observation only, whereas those with high uPA and/or PAI-1 values were randomised to receive either CMF or observation. The 10-year follow-up updated analysis showed that: low-risk N0 patients according to the uPA/PAI1, thus without any systemic therapy, had an excellent prognosis, with a 10-year survival rate of almost 90% [19], while the high-risk patients according to the uPA/PAI-1 had a 1.84fold higher disease recurrence risk (P = 0.017) than the lowuPA/PAI-1. Additionally, the assay predicted, in the high-risk population, the benefit from CT [20]. These results provide for the first time long-term follow-up from a prospective biomarker-driven clinical trial in cancer. The Node-Negative Breast Cancer (NNBC)-3 study is a prospective multicentre phase III therapy trial, with the aim of comparing risk assessment and clinical outcome on the basis of tumour-biological factors uPA/PAI-1 with those based on established, clinical and pathomorphological factors in high-risk node-negative BC patients. It enrolled more than 4000 patients, stratified into low-risk and high-risk groups according to the uPA/PAI-1 value or according to the clinical pathological algorithm. Those classified as low risk did not receive CT, whereas those classified as high risk received either six cycles of FEC or three cycles of FEC and three cycles of docetaxel [21]. In the West German Study Group Plan B trial, a prospective comparison of recurrence score (RS) – OncotypeDx – and independent central pathology assessment of prognostic tools was performed. The study randomised 2361 patients; 18% had a recurrence score of 0–11 (low risk), 61% had a recurrence score of 12–25 (intermediate risk), and 21% had a recurrence score of >25 (high risk). A weak correlation was found between uPA/PAI-1 and RS. These data showed that high-risk status according to RS is well correlated with high risk by uPA/PAI-1; however, there was substantial heterogeneity in risk assessment in the low- and intermediate-risk RS groups in which some patients are still considered to be high risk according to uPA/PAI-1 [22].

2.2.

Gene-expression-based assays

Gene expression profiling has identified several molecular signatures that mostly have prognostic value and some prediction value.

2.2.1.

First-generation prognostic signatures – MammaPrintTM

MammaPrintTM is a microarray-based gene-expression-profiling assay that measures the levels of expression of 70 genes related to proliferation, invasion and angiogenesis. The assay accurately categorises patients in poor and good prognosis

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groups on the basis of the development or not of distant metastases within 5 years. Initially requiring fresh or frozen samples, it can now be effectively performed in formalinfixed paraffin-embedded specimens (FFPE). The initial data were derived from 78 patients with nodenegative BC, 65 cm, the vast majority of whom had ER-positive tumours and did not receive adjuvant systemic treatment [23]. The validation cohort included 295 node-negative patients, of whom 61 were from the initial study, and confirmed MammaPrintTM independent prognostic value beyond standard clinicopathological variables in this patient population [24]. The TRANSBIG consortium carried out an independent retrospective validation of MammaPrintTM using samples from nine European countries, which further confirmed the prognostic value of this tool [25]. Additional validation studies were performed in node-positive EBC patients [26] and in HER2+ EBC patients [27]. MammaPrintTM is the first FDA-approved gene-expressionbased assay to be used as a prognostic test in EBC patients. The clinical utility of this assay is being prospectively evaluated in the large, randomised MINDACT trial that enrolled 6690 EBC N0–N3 patients [28].

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While waiting for MINDACT and TAILORx results, international recommendations support the selected use of MammaPrintTM and Oncotype DxTM in the ER + EBC patients in whom standard clinical/pathological factors are considered insufficient for adjuvant CT decisions.

2.2.3.

Oncotype DxTM recurrence score

Oncotype DxTM is a quantitative reverse transcriptase–polymerase chain reaction- (qRT–PCR-) based signature that measures the expression of 21 genes (16 cancer-related and five reference genes), performed using RNA from FFPE tumour tissues. With this multigene predictor assay a mathematical function (named recurrence score, RS) aiming at predicting the risk of distant relapse for patients with ER-positive, lymph-node-negative breast cancer treated with tamoxifen was developed based on the analysis of clinical samples from the NSABP B-20 clinical trial [29]. The RS is a continuous variable, ranging from 0 to 100, which translates into three riskgroup categories: low (RS < 18), intermediate (RS from 18 to 240 mg/m2 of doxorubicin or 360 mg/m2 of epirubicin) [96]. The improvement in the risk of recurrence, breast cancer or overall mortality was present only with the use of higher cumulative doses of anthracyclines (Table 2). This suggests that a real difference between these regimens exists but is limited to anthracycline regi-

Table 1 – Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview results comparing adjuvant chemotherapy (CT) with no CT in early breast cancer (EBC). Risk of recurrence

Breast cancer mortality

Overall mortality

Anthracycline-based regimen versus no CT RR: 0.73, 95% confidence interval (CI) Absolute gain: 8%

RR: 0.79, 95%CI Absolute gain: 6.5%

RR: 0.84, 95%CI Absolute gain: 5%

Cyclophosphamide, methotrexate and fluorouracil (CMF) regimen versus no CT RR: 0.70, 95%CI Absolute gain: 10.2%

RR: 0.76, 95%CI Absolute gain: 6.2%

RR: 0.84, 95%CI Absolute gain: 4.7%

8

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mens containing three agents (e.g. CEF, CAF) and given for at least six cycles. Standard dosing of anthracycline-based therapy (four cycles of a two-drug regimen, e.g. 4AC) seems to be equivalent to CMF.

4.2.1. Anthracyclines versus Anthracylines + taxane based therapy

AC, doxorubicin and cyclophosphamide; CAF, cyclophosphamide, doxorubicin, and fluorouracil; EC, epirubicin and cyclophosphamide; A, doxorubicin; E, epirubicin.

Overall mortality RR: 0.97 (P = 0.55) BC mortalitiy RR: 0.98 (P = 0.67) Recurrence RR: 0.99 (P = 0.76)

Overall mortality RR: 0.84 (P = 0.0002) BC mortalitiy RR: 0.80 (P = 0.00001) Recurrence RR: 0.89 (P = 0.003)

48 Node-negative and node-positive EBC (n = 2391) NEAT/BR969

60 Node-positive premenopausal EBC (n = 466) Mam-1 GOCSI

50 Node-positive EBC (n = 777) Belgian study

60 Node-negative,ER-negative EBC (n = 2008) NSABP B-23

EBCTCG Overview: anthracyclines versus CMF Standard-strength anthracycline-based regimen versus standard or near-standard CMF Low-strength anthracycline-based regimen versus standard or near-standard CMF

HR: 0.79 P = 0.31 82% versus 75% P < 0.001 82% versus 75% P < 0.001 76% versus 69% P < 0.001

92% versus 90% P = 0.03 90% versus 89% P = 0.4 85% versus 86% 85% versus 82% P = 0.03 87% versus 87% P = 0.9

CAF · 6 CMF · 6 AC · 4 CMF · 6 CMF · 6 EC · 8 full dose A ! CMF CMF E · 4 ! CMF · 4 versus CMF · 6/8 Node-negative high risk EBC (n = 2691) INT 0102

60

Disease-free survival(DFS) (P-value) Treatment Median follow-up Population (n) Study

Table 2 – Adjuvant anthracycline versus cyclophosphamide, methotrexate and fluorouracil (CMF) trials in early breast cancer (EBC).

Overall survival (OS) (P-value)

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The role of taxane-base CT as adjuvant treatment of EBC is an extensively studied but still controversial issue. We currently have 21 clinical trials of first-generation taxanes, several pooled analyses, meta-analyses, and since 2012 the role of these agents is also evaluated in the analysis of the EBCTCG overview. Some of the key first-generation taxane trials are presented in Table 3. When analysing the 12 first-generation trials using low-strength anthracycline reference regimens, eight suggest a benefit in terms of DFS for the taxane regimen (CALGB 9344; NSABP B-28; the MD Anderson Neoadjuvant Trial; FinHER; BCIRG 001; HORG; GEICAM 9805; US Oncology Group 9735) and only three of the 10 trials that reported survival showed a benefit in OS (CALGB 9344, BCIRG 001, and US Oncology 9735). Several pooled analyses and meta-analyses have been undertaken aiming to clarify the benefit of taxane-based therapy (Table 3). Overall they support a modest improvement in DFS and overall survival (5% and 3% absolute benefit, respectively) when taxane-based regimens are compared with standard anthracycline polychemotherapy, irrespective of the type of taxane, schedule of administration, extent of nodal involvement and hormone-receptor expression status [97]. In the EBCTCG 2012 meta-analysis the incorporation of a taxane into an anthracycline CT regimen resulted in reduction in the recurrence risk, risk of breast cancer and overall mortality (Table 3) independently of age, nodal status, tumour size, tumour grade or ER status. However, we must underscore that treatment comparisons varied greatly, which complicates the analysis. In this regard, the effect of taxanes was analysed taking into account how the CT regimen in the control group compared with the non-taxane CT in the taxane group (same, doubled or intermediate). The major effect of these agents was seen in the trials where the same control regimen was used in both arms (n = 11,167 women) with a reduction in the risk of recurrence, breast cancer and overall mortality that translated into an absolute gain of 4.6%, 2.8% and 3.2%, respectively [96]. When considering this benefit we must acknowledge that in these trials a ‘week’ anthracycline-based regimen was used and greater treatment duration was obtained with the additional four cycles of a taxane to the anthracycline regimen. As a matter of fact, when the number of cycles in the control anthracycline regimen was doubled (to mirror the addition of four cycles of taxanes to anthracyclines in the experimental arm) there was little difference in recurrence, breast cancer or overall mortality (Table 3).

4.2.2.

HER2 positive breast cancer

The optimal anti-HER2 adjuvant treatment will be addressed below

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Table 3 – Adjuvant taxane trials in early breast cancer (EBC). Study

Median follow-up (months)

Treatment

‘‘Low-strength’’ sequential anthracycline CALGB 9344 Node-positive EBC (n = 3170)

69

NSABP B-28

Node-positive EBC (n = 3060)

34

MDACC

EBC (n = 524)

60

NSABP B-27

T1–T3 operable BC (n = 2411)

102

AC · 4 versus AC · 4 – 7 years: 64% versus Pac · 4 58% (HR: 0.83; P = 0.001) AC · 4 versus AC · 4 – 5 years: 76% versus Pac · 4 72%; (HR: 0.83; P = 0.002) FAC · 8 86% versus 83% (HR: Pac · 4 – AC · 4 0.70; P = 0.009) S ! AC ! Doc versus 71% versus 68% (HR: S ! AC 0.92; P = 0.29) AC ! S ! Doc versus 70% versus 68% (HR: S ! AC 0.92; P = 0.29)

83% versus 82% (HR: 0.93; P = 0.46) 82% versus 83% (HR: 0.97; P = 0.7)

‘‘Low-strength’’ concurrent anthracyclinea BCIRG-001 Node-positive EBC 124 (n = 1491) GEICAM 9805 Node-negative EBC 77 (n = 1060)

DAC · 6 FAC · 6 DAC · 6 FAC · 6

62% versus 55%, P = 0.0043 87.8% versus 81.8% (HR: 0.68; 95%CI; P = 0.01)

76% versus 69%, P = 0.002 95.2% versus 93.5% (HR: 0.76; 95%; P = NS)

‘‘Standard strength’’ sequential anthracycline* GEICAM 9906 Node-positive EBC 66 (n = 1246) PACS 01 Node-positive EBC 60 (n = 1999)

FECq3w · 6 FEC · 3 – Pac · 8w FECq3w · 6 FEC · 3 – Doc · 3w

78% versus 72% (HR: 0.74; P = 0.006) 78% versus 73% (HR: 0.82; P = 0.034) Estimated 5 years EFS 91% versus 85% (HR: 0.58, P = 0.004)

90% versus 87% (NR; P = 0.11) 91% versus 87% (HR: 0.73; P = 0.014)

WGSG/AGO EC-Doc Trial

Population

1–3 Positive lymph node (n = 2011)

Meta-analysis Meta-analysis 13 Studies EBC (n = 22,903)

DFS (P-value)

41

4 · EC – 4 · Doc 6 · FEC100 6 · CMFb

–

–

OS (P-value)

7 years: 74% versus 68% (HR: 0.82, P = 0.01) 5 years: 85% versus 85% (HR: 0.93; P = 0.46) NR

Estimated 5 years OS 95% versus 91% (P = 0.03)

HR: 0.83 (95%CI, 0.79– HR: 0.85 (95%CI, 0.79– 0.87; P < 0.00001) 0.91; P < 0.00001)

EBCTCG overview – taxane-plus-anthracycline versus anthracycline-based regimen Results for all trials that test taxane Distant recurrence RR: 0.87 effect (n = 44,000) Any recurrence RR: 0.86 (P = 0.00001) 8-year recurrence: Unconfounded trialsa (taxane versus control group) 30.2% versus 34.8% (absolute gain 4.6%) Counfounded trialsa 8-year recurrence: (taxane versus control group) 19.2% versus 22% (absolute gain 2.9%)

BC mortality RR: 0.87 (P = 0.00001) Other mortality RR: 0.99 8-year BC mortality: 21.1% versus 23.9% (absolute gain 2.8%) 8-year BC mortality: 10.1% versus 11.5% (absolute gain 1.4%)

Overall mortality RR: 0.89 (P = 0.0001) 8-year overall mortality 23.5% versus 26.7% (absolute gain 3.2%) 8-year overall mortality 11.2% versus 12.4% (absolute gain 1.2%)

FEC, cyclophosphamide, epirubicin, and fluorouracil; AC, doxorubicin and cyclophosphamide; Pac, paclitaxel; FAC, fluorouracil, doxorubicin and cyclophosphamide; Doc, docetaxel; S, surgery; DAC, docetaxel, doxorubicin, cyclophosphamide; EC, epirubicin and cyclophosphamide; CMF, cyclophosphamide, methotrexate, and fluorouracil. a Anthracycline-based adjuvant breast cancer regimens are categorized into ‘standard-strength’ and ‘low-strength’ regimens based on cumulative doses of doxorubicin >240 mg/m2 and epirubicin >360 mg/m2. Example: standard strength: FEC100; FEC90; CEF; CAF:A75 or E100 followed by CMF; reduced strength: FEC75; FEC60; FEC50; FAC; AC; EC.

4.3. Should anthracyclines be avoided in the adjuvant setting? Anthracyclines are amongst the most active chemotherapeutic agents for the treatment of breast cancer. Multiple trials in the past two decades demonstrated that anthracycline-based chemotherapy was associated with lower rates of breast cancer recurrence and improved survival when compared with

non-anthracycline chemotherapy regimens, such as CMF [96]. However, these agents are associated with increased risk of cardiovascular complications, dependent on cumulative dose and schedule, and are often irreversible. The benefit of taxanes when incorporated into the adjuvant setting for women with newly diagnosed breast cancer was analysed in several trials and has been discussed above. It is, however, unknown whether the benefit seen from add-

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ing a taxane in the adjuvant setting will obviate the need for anthracyclines in a subset of patients, since the great majority of studies evaluated the addition of a taxane to an anthracycline regimen and not its replacement. A phase III randomised trial, the US Oncology Research Trial 9735 [98], enrolled 1016 women with stages I–III HER2-negative breast cancer and randomly assigned therapy with four cycles of AC or four cycles of docetaxel plus cyclophosphamide (TC). With a median follow-up of 7 years, TC resulted in a significantly higher DFS (81% versus 75%) and OS (87% versus 82%). However, how the TC regimen compares with stronger anthracycline-based regimens such as FEC/FAC and with third-generation regimens, which incorporate both an anthracycline and taxane, is still unknown. Therefore, most international guidelines continue to recommend an anthracycline- and taxane-containing regimen for most women, particularly those with higher-stage tumours, and for those with triple-negative or HER2+ BC, unless there are clear contraindications for the use of anthracyclines [13]. The role of anthracycline regimens in the HER2+BC is also a matter of intense research. Several CT regimens used with trastuzumab have been evaluated in large prospective studies, and historically anthracyclines have been considered critical for the management of HER2+ BC. A number of studies from the pre-trastuzumab era support this concept. Retrospective subset analyses of anthracycline-based adjuvant CT studies have suggested that the major benefit for these regimens is seen in HER2-over-expressing tumours [99]. The value of HER2 and TOP2A as predictive markers of response to anthracycline-based therapy has been extensively studied. In the meta-analysis by Di Leo et al., although HER2 amplification and combined TOP2A amplification and deletion had some value in prediction of responsiveness to anthracycline-based therapy, the overall findings did not support the routine use of TOP2A to select the adjuvant CT regimen in this patient population [78]. With the advent of trastuzumab, concerns have been raised regarding the use of anthracycline-based regimens in HER2+ early BC due to potential cardiotoxicity. Previous or concurrent anthracyclines are a risk factor for trastuzumabrelated cardiotoxicity. Notwithstanding the increased incidence of cardiac events, these still remain in very acceptable ranges for all types of CT regimens used in the adjuvant setting. Rates of severe congestive heart failure in adjuvant trials ranged between 0.4% and 3.5%, depending on the regimen and schedule used. Combining trastuzumab with a non-anthracycline-containing CT regimen was evaluated in the BCIRG 006 trial with the aim of investigating whether the association of trastuzumab, carboplatin and docetaxel could be better tolerated and superior in terms of efficacy compared with an anthracycline-based schedule [79]. At a median follow-up of 65 months, the differences in DFS and OS between ACTH and TCH, although not statistically significant, were numerically different, with a trend favouring the anthracycline-containing regimen. The trial hypothesis that TCH was superior to ACTH was not proven and, since the study was not powered to detect equivalence between ACTH and TCH, this conclusion cannot be drawn. With respect to adverse events, the differences were significantly lower rates of severe (grade )

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neutropenia (66% versus 63%) and leucopaenia (48% versus 60%) but significantly higher rates of anaemia (6% versus 3%) and thrombocytopenia (6% versus 2%) for TCH and a higher incidence of congestive heart failure (2% versus 0.4%), subclinical and sustained loss of mean left ventricular ejection fraction (18.6% versus 9.4%) for ACTH. Based on this trial alone, TCH can only be considered an alternative treatment for patients with contraindications to anthracyclines (pre-existing cardiac conditions, borderline ejection fraction at baseline, or prior anthracycline exposure) while anthracycline-based regimens remain the standard of care. Findings suggest that the more dramatic risk reduction when adding trastuzumab to CT is observed when using some concurrent CT and trastuzumab, and employing both anthracycline and a taxane.

4.4.

Dose-dense adjuvant chemotherapy

The introduction of granulocyte-colony-stimulating factors has allowed the administration of CT in the dose-dense approach, thought to have higher efficacy based on mathematical models of human breast cancer growth [100]. The pivotal trial CALGB9741 [101] has shown significant improvement in DFS and OS with dose-dense concurrent AC followed by paclitaxel in women with node-positive EBC. Several trials with dose-dense regimens have shown similar results, as shown in a systematic review and meta-analysis of these studies [102] with HR of death 0.85 (95%CI = 0.77–0.93) and HR of relapse or death 0.81 (95%CI = 0.75–0.88). Another important finding was that the benefit was seen only in hormonal-receptor-negative disease. There was no statistically significant increase in adverse events. The concern about these results is related to the design of these trials that did not evaluate the same agents and doses in the conventional arm as in the investigational arm. Further prospective data will help to clarify which patients should be selected for this approach. At the moment these regimens have been mainly used in high-risk disease with features of aggressive biology.

4.5.

Sequential versus combination regimens

Sequential single-agent doxorubicin and cyclophosphamide did not improve outcome compared with combination AC [103]. Sequential versus concurrent use of anthracyclines and taxanes in EBC has been evaluated in three studies: CALGB 9741, BIG 2-98 and NSABP B-38. The first study, CALGB 9741 [101], randomised 2005 female patients, with node-positive disease, to sequential A · 4 ! T · 4 ! C · 4, every 3 weeks; A · 4 ! 3 T · 4 ! C · 4, every 2 weeks with filgrastim; concurrent AC · 4 ! T · 4, every 3 weeks or AC · 4 ! T · 4, every 2 weeks with filgrastim. Dose-dense treatment was associated with improved DFS and OS, with no increase in toxicity. In the BIG-2-98 [104] study 2887 patients, also with nodepositive disease, were randomised to sequential A · 4 ! CMF · 3 (sequential control); concurrent AC · 4 ! CMF · 3 (concurrent control); sequential A ! T · 4 ! CMF · 3 (sequential experimental); concurrent AT · 4 ! CMF · 3 (concurrent experimental). The updated analysis [105] revealed that sequential docetaxel was associated with significant

EJC SUPPLEMENTS

improvement of DFS compared with control arms and with concurrent AT. Preliminary results of NSABP B-38 were recently presented [106]. The trial randomised 4894 women (65% node-positive) to dose-dense ACT, dose-dense AC followed by the combination of paclitaxel and gemcitabine (ACTG), or TAC. Five-year DFS and OS were similar between groups, but the TAC regimen was associated with more grade 3/4 toxicity, namely febrile neutropenia and diarrhoea. Based on the tolerability profile, and on the possible higher efficacy, sequential anthracycline–taxane-based regimens are preferred to combination regimens.

4.6. Are there predictive biomarkers to help select the optimal regimen? Identification of markers that predict chemosensitivity in BC is a research priority. Several approaches and technologies have been used to identify these predictive markers. The aim is to answer two questions: (a) can we use gene signatures to identify tumours, which are more likely to respond to chemotherapy? and (b) when chemotherapy is indicated, what is the optimal chemotherapy regimen for a specific tumour or group of tumours?

4.6.1.

Markers predicting general chemosensitivity

Since patients with poor prognosis disease defined by firstgeneration signatures have tumours with high expression of proliferation-related genes, and cytotoxic agents target the proliferating fraction of tumours, the finding that first-generation prognostic signatures also predict benefit from conventional multidrug CT regimens is not surprising [45,107–110]. With respect to OncotypeDx, two retrospective studies have reported its predictive value for chemosensitivity [32,111]. In the NSABP trial B-20, 651 patients with node-negative, hormone-receptor-positive tumours were randomised to tamoxifen alone (n = 227) or tamoxifen plus CT (methotrexate–fluorouracil or CMF) (n = 424) [32]. A high recurrence score predicted benefit from CT [hazard ratio (HR) = 0.26; 95% CI = 0.13–0.53], with little or no benefit from CT in the low and intermediate recurrence score groups. The predictive value of the OncotypeDx was also assessed in a subset of patients more than 50 years old with node-positive hormonereceptor-positive tumours included in the SWOG 8814 trial [111]. In this trial, patients were randomised to receive either tamoxifen alone (n = 361); CAF followed by tamoxifen for 5 years (n = 566); or concurrent CAF and tamoxifen (n = 550). The 21-gene recurrence score was assessed in 367 of these patients. The addition of CT to tamoxifen resulted in no difference in DFS or OS in the low recurrence score group, but a clear benefit in DFS and OS in the high recurrence score group. There appeared also to be a benefit for patients in the intermediate recurrence score group, but the confidence intervals were wide due to the small sample size. This signature was assessed in a series of 167 patients with tumours >5 cm or clinically positive nodes and has also been suggested to predict the response to neoadjuvant CT [112]. Pathological complete response (pCR) after neoadjuvant CT was used as a surrogate for chemosensitivity and in this trial

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11

only patients with a bad signature achieved a pCR of 20% (29/ 144). None of the patients with a good signature (n = 144) achieved a pCR (0/23). The authors concluded that patients with a good signature would be unlikely to respond to CT.

4.6.2.

Markers predicting drug-specific chemosensitivity

There are currently no biomarker predictors of response to specific cytotoxic agents. There are several reasons for the apparent inability to develop these predictive factors, namely: (a) resistance or response to therapies may be caused by a functional alteration in only a few genes and this may not manifest itself as a detectable signal in the complex transcriptomic landscape of a tumour; (b) tumours are often composed of a mosaic of genetically heterogeneous clonal subpopulations harbouring numerous private genetic aberrations (that is, aberrations found in a single clone of a tumour [31,113]. These private genetic aberrations may be the drivers of resistance to therapy in a subpopulation and would not be detected by microarrays that survey the average expression profile of the entire tumour. The Topoisomerase II Alpha Gene Amplification and Protein Overexpression Predicting Efficacy of Epirubicin (TOP) trial (NCT00162812) led to the development of the anthracycline-based score (A-score), which combines three predictive signatures: a TOP2A gene signature and signatures related to tumour invasion and immune response [74]. Analysis of the predictive power of the A-score was performed in the EORTC 10994/BIG (Breast International Group) 00-01 (NCT00017095) trial and from ER-negative patients from the Randomised Clinical Trial to Evaluate the Predictive Accuracy of a Gene Expression for Stage I–II Breast Cancer (NCT00336791). Both studies revealed its high negative predictive value (0.98, 95%CI 0.90–1.00) [74] suggesting, if validated, its potential clinical use for identification of patients who are unlikely to benefit from anthracyclines.

5. What is the optimal adjuvant endocrine treatment? 5.1.

Tamoxifen 5 years

Endocrine therapy (ET) is one of the most effective treatments in women with endocrine responsive breast cancer. Tamoxifen has been the mainstay endocrine agent for both preand postmenopausal women. Updated analyses [114] of the EBCCTG overview assessed long-term outcomes among 21,475 women with EBC in trials of 5 years of tamoxifen compared with observation or placebo. In oestrogen-receptor- (ER)positive disease, 5 years of tamoxifen significantly reduced recurrence rates throughout the first 10 years, independently of progesterone receptor status, nodal status, or use of CT: relative risk (RR) 0.53 during years 0–4 and RR 0.68 during years 5–9 [both 2P < 0.00001]. For marginally ER-positive disease there was also an important risk reduction (RR 0.67). More importantly there was a reduction in breast cancer mortality by about a third throughout the first 15 years (RR 0.71 during years 0–4, 0.66 during years 5–9, and 0.68 during years 10– 14; P < 0.0001).

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5.2. Ovarian suppression and aromatase inhibitors for premenopausal patients The standard adjuvant hormonal therapy in premenopausal women with ER-positive disease remains tamoxifen alone for 5 years, but benefit has also been shown with the use of luteinising-hormone-releasing (LHRH) agonists specifically in the absence of CT. Several studies have been conducted testing LHRH agonists alone, combined with tamoxifen, chemotherapy or both. In the EBCTCG overview [115] 8000 patients randomised to ovarian function suppression (OFS) or ablation by surgery/radiation had reduced recurrence and breast cancer mortality, but the benefit was seen mainly in the absence of other systemic treatments. An individual patient data meta-analysis [116] of 16 trials using LHRH identified 9022 women with ER+ disease and assessed recurrence rate, breast cancer mortality and overall mortality. While LHRH agonists alone did not have a significant effect, adding these agents to CT, to tamoxifen or both, significantly reduced recurrence by 12.7% (P = 0.02) and death after recurrence by 15.1% (P = 0.03). Furthermore, the benefit of LHRH agonists after CT was seen in women younger than 40 years, but not in older premenopausal women. However, the data do not answer the question of whether LHRH agonist is useful only when amenorrhoea is not achieved with CT, an event that has been associated with worse outcome in some trials [117,118]. Recently a guideline from Cancer Care Ontario was published and endorsed by ASCO [119] conducting a systematic review of available literature. The guideline does not recommend the routine use of OFS added to chemotherapy, tamoxifen or a combination of both. It does acknowledge as a major difficulty in assessing its efficacy the fact that ovarian suppression has not been compared with current CT regimens (e.g. anthracyclines or anthracyclines/taxanes), which deems the benefit of these agents unclear. For chemical suppression the guideline does suggest the use of monthly injections. The role of aromatase inhibitors (AIs) in premenopausal women was assessed in the ABCSG-12 trial [120] which randomised 1803 patients to receive goserelin monthly plus tamoxifen or anastrozole, with or without zoledronic acid for 3 years. There was no significant difference in DFS between the anastrozole and tamoxifen groups (HR = 1.10; CI 0.78–1.53), but the trial was relatively small to answer this secondary objective. Till now AIs combined with OFS are only recommended in premenopausal patients if tamoxifen is contraindicated. To better understand the role of aromatase inhibitors, as well as OFS in this setting, results from the studies TEXT, SOFT and PROMISE are eagerly awaited.

5.2.1.

Aromatase inhibitors

For postmenopausal patients the aromatase inhibitors anastrozole, letrozole and exemestane have been extensively studied in adjuvant setting as upfront therapy for 5 years, ‘‘switch’’ strategy of initial tamoxifen for 2–3 years followed by an AI 2–3 years, the reverse sequence, or as an extended treatment after 5 years of tamoxifen (see Table 4) [121–129]. The meta-analysis of the adjuvant trials [130] analysed a cohort of 9856 patients where AI upfront therapy was compared

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with standard tamoxifen treatment, showing a significant 2.9% absolute decrease in recurrence and a non-significant absolute 1.1% decrease in breast cancer mortality. A second cohort comprising 9015 patients compared the switch strategy with standard tamoxifen treatment and showed a significant absolute decrease in recurrence and in breast cancer mortality of 3.1% and 0.7%, respectively. Current ASCO [131] and European Guidelines [132] recommend the incorporation of AIs in the endocrine treatment plan as switch (2–3 years) or upfront therapy strategy (5 years). For patients who have completed 5 years of tamoxifen the addition of an AI for a further period of 2–5 years is recommended, especially for patients with node-positive disease. On the other hand, 5 years of tamoxifen alone is still a viable option for certain patients at very low risk of recurrence. The choice of endocrine treatment and the timing for AI treatment is nowadays based on the toxicity profile of these drugs compared with tamoxifen, general health issues of each individual and the risk of relapse. A recent meta-analysis [133] on safety reports from major adjuvant trials found that AI therapy was associated with a higher risk for cardiovascular disease (HR, 1.2) and bone fracture (HR, 1.48) than tamoxifen, but a lower risk for venous thromboembolism (HR, 0.53) and uterine cancer (HR, 0.32). Overall these risks were low, around 2% of patients, and fractures only occurred in fewer than 10% of all patients. Additional data from a population-based study [134] evaluating 44,000 women with breast cancer and age-matched women without breast cancer, have shown that breast cancer patients on ET had a lower risk for both myocardial infarction and ischaemic stroke than those who did not have breast cancer. No differences were seen between AI therapy and tamoxifen therapy in the risk for myocardial infarction or stroke, but AI therapy was associated with a higher risk for any fracture (mainly hip fractures). Guidelines [131,132] recommend surveillance of bone mineral density during AI treatment, and calcium and vitamin D supplementation or a bisphosphonate depending on the result.

5.3.

Extended ET treatment

Because the risk of recurrence in hormone-receptor-positive disease still remains after the first decade [135], clinicians and researchers have been questioning the benefit of extended tamoxifen treatment beyond 5 years. Three prospective trials addressed this question, randomising patients after 5 years of tamoxifen treatment to additional 5 years of treatment or placebo (NSABP-B14 [136], aTTom trial [137] and ATLAS trial [138]). Except for the NSABP B14 trial, these studies together with EBCCTG [114] have shown benefit for extended tamoxifen. However, balance with side effects has to be considered as extended treatment is associated with increased incidence of endometrial cancer, which is 2.3-fold with 5 years of tamoxifen and 4-fold with 10 years [114]. On the other hand, there is some evidence that tamoxifen has a favourable effect in lipid profile [139–141]. ATLAS results suggest some protection against ischaemic heart disease and certainly no increase in stroke deaths. In the EBCCTG overview the non-significant excess of stroke deaths was balanced by a non-significant shortfall in cardiac deaths with lit-

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Table 4 – Trials of adjuvant endocrine therapy. Study Tamoxifen 5 years Overview 2011 (W164)

OFS Overview 2005 [115]

Meta-analysis [164]

AIs 5 years ATAC [164]

BIG 1.98 [164]

TEAM [164]

Meta-analysis [164]

MA.27 [6]

Treatment arms/ population (n)

Median follow-up

Recurrence

Mortality

TAM 5 years versus no TAM 10,645 ER+

15 years

RR = 0.53 [SE 0.03] years 0–4 RR = 0.68 [SE 0.06] years 5–9 2P < 0.00001 RR = 0.97 [SE 0.10] years 10–14

RR = 0.71 [SE 0.05] years 0–4 RR = 0.66 [SE 0.05] years 5–9 RR = 0.68 [SE 0.08] years 10–14 P < 0.0001

8000 ER+/ER unknown, 0.9

HR = 0.93 (95%CI 0.77– 1.13) P = 0.46

71 months

HR = 1.05 (95%CI 0.84– 1.32) HR = 0.96 (95%CI 0.76– 1.21)

HR = 1.13 (95%CI 0.83– 1.53) HR = 0.90 (95%CI 0.65– 1.24)

28 months

HR = 0.60 (0.44–0.81) P = 0.0009

P = 0.16

(continued on next page)

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Table 4 – (Continued) Study

Treatment arms/ population (n)

Median follow-up

Recurrence

Mortality

ITA [122]

TAM 5 years versus Tam f 2 years followed by ANA TAM 5 years versus Tam f 2–3 years followed by EXE 2– 3 years Cohort 2 AIs T after 2–3 years of TAM versus TAM 9015

128 months

HR = 0.64 (0.44–0.94) P = 0.023

HR = 0.72 (0.44–1.17) P = 0.3

55.7 months

HR = 0.76 (95%CI 0.66– 0.88) P = 0.0001

HR 0.85 (95%CI 0.71– 1.02) P = 0.08

3.9 years

5.0% AI versus 8.1% TAM 3.1% absolute decrease (SE 0.6%) 2P < .00001

1.7% AI versus 2.4% TAM 0.7% (SE = 0.3%) absolute decrease 2P = 0.2

NR

RR = 0.90 (95%CI 0.79– 1.02) 5–9 years RR = 0.75 (95%CI 0.62– 0.90) later years RR: 0.84, 95%CI 0.76– 0.94; P = 0.002 in ER+ DFS = 82% TAM 5 years versus 78% TAM >5 years P = .03 415 TAM 5 years versus 442 recurrences TAM 10 years RR = 0.94 (95%CI 0.81– 1.09) P = 0.4 HR = 0.58 (95%CI 0.45– 0.76) P < .001

RR = 0.97 (95%CI 0.79– 1.18) 5–9 years RR = 0.71 (95%CI 0.58– 0.88) later years 639 deaths versus 722 deaths, P = 0.01 in ER+ OS7Y = 94% TAM 5 years versus 91% TAM >5 years P = .07 NA

IES [124](164)(164) (164)

Meta-analysis [130]

Extended treatment beyond 5 years ATLAS [138] TAM 5 years versus TAM 10 years 3428/3418

NSABP-B14 [136]

TAM 5 years versus TAM >5 years 579/593

7 years

aTTOM [137]

TAM 5 years versus TAM 10 years 6934

4.2 years

MA.17 [143]

TAM 5 years followed LET 5 years versusTAM 5 years 2594/2593 TAM 5 years followed EXE 5 years versus TAM 5 years 779/786 TAM 5 years followed ANA 3 years versus TAM 5 years 469/387

30 months

NSABP-B33 [164]

ABCSG-6a [165]

HR = 0.82(95%CI 0.57– 1.19) P = 0.03

30 months

DFS 4 years 91% versus 89% RR = 0.68 (P = 0.07)

16 deaths versus 13 P = 0.1

62 months

HR = 0.62 (95%CI 0.40– 0.96) P = 0.031

HR = 0.89 (95%CI 0.59– 1.34) P = 0.57

AI, aromatase inhibitor; DFS, disease-free survival; ER+, estrogen-receptor-positive patients; HR, hazard ratio; RR, event rate ratio; OS, overall survival; TAM, tamoxifen; LET, letrozole; EXE, exemestane; ANA, anastrozole; LHRH, luteinizing-hormone-releasing agonists; OFS, ovarian function suppression.

tle net effect on overall vascular mortality. Interestingly, a recent study [142], with a median follow up of 10.1 years, assessed the long-term benefits of 5 years versus 2 years of tamoxifen use in a large randomised trial of EBC women more than 50 years of age. Follow-up strategies included matching trial subjects with death data from the British National Health Service Information Center. Besides the well-known positive efficacy of tamoxifen, this study revealed a nearly statistically significant reduction in cardiovascular deaths (HR, 0.79; P = 0.08) with longer tamoxifen, and in women of 50–59 years there was an even greater reduction in cardiovascular events

(HR, 0.65; P = 0.005; P = 0.046 for interaction between age and treatment groups). In postmenopausal women extended use of AIs after 5 years of tamoxifen has shown improvement in DFS (see Table 4), and in one study, the MA-17 trial [143], an improvement in OS was also seen in node-positive patients. It is not known if longer use of AIs (more than 5 years) will increase outcomes without compromising safety, and it is not recommended until mature data from MA.17R and NSABP B-42 trials are available. The best regimen of ET for postmenopausal patients and the duration of ET treatment are still unanswered questions.

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Table 5 – Phase III trials of adjuvant trastuzumab in patients with HER2-positive early breast cancer (EBC) Study

Population

Median follow-up (months)

Treatment

DFS (P-value)

OS (P-value)

Cardiac dysfunction (%)

HERA [156]

Node-positive or node-negative high-risk EBC after completion of standard CT (n = 5.090) Node-positive Node-negative high-risk EBC (n = 4046) Node-positive Node-negative high-risk EBC (n = 1.944) Node-positive Node-negative high-risk EBC (n = 3,222)

96

No additional therapy H 1 year H 2 year

HR = 0.76, P < 0.0001

HR = 0.76, P = 0.0005

0.8 3.7

100.8

AC!Pac AC!Pac!H

62.2% 73.7% (P < 0.001) HR = 0.6

63.6

AC!PacH AC!Pac!H

84% (5 years) 80% (P = 0.0216) HR = 0.77

75.2% 84.0% (P < 0.0001) HR = 0.63 NR NR

17 14

65

AC!Doc AC!Doc-H Doc–Carb–H

75% 84% HR = 0.64 (P < 0.001 versus CT) 81% HR = 0.75 (P < 0.04 versus CT)

NSABP B-31/ NCCTG N9831 [157] NCCTG N9831 [161]

BCIRG 006 [79]

PACS-04 [159]

Node-positive EBC

47

FEC or Epi–Doc FEC or Epi–Doc!H 1 year

78% (3 years) 81% (P = 0.41)

FinHER [158]

Node-positive Node-negative high-risk EBC (n = 232) All trials included

62

Doc or Vin !FEC Doc or Vin !FEC–H

73.3% 83% HR = 0.65 (P = 0.12)

Meta-analysis 2012 [160]

HR: 0.60; 95% P < 0.00001

87% 92% HR = 0.63 (P < 0.001 versus CT) 87% HR = 0.77 (P < 0.038 versus CT) 96% (3 years)v 95% (P = 2.38)

9.0 18.1 8.6

2.2 4.2

82.3% 91.3% (5 years) HR = 0.55 (P = 0.094) HR: 0.66; 95% P < 0.00001

FEC, cyclophosphamide, epirubicin, and fluorouracil; AC, doxorubicin and cyclophosphamide; Pac, paclitaxel; Doc, docetaxel; S, surgery; H, herceptin; Carb, Carboplatin; Vin, vinorelbin; Epi, epirubicin.

5.4. Compliance to hormonal therapy and predictors of response to treatment Adherence to ET is a concern in patients with EBC as it is believed to impact on the outcome; however, the association between non-adherence and breast cancer mortality is not proven. In ET studies patients are considered to be adherent to treatment if P80% of prescribed doses are taken, but the best tool for measurement of adherence is not yet defined, and has varied among studies. It has been reported that adherence to tamoxifen falls to 50% during the course of therapy [144]. Non-adherence to anastrozole has been reported to occur in 1/3 of patients [145]. In a recent population-based study of 8769 patients with BC [146], 32% discontinued treatment with tamoxifen or an AI over the 4.5-year follow-up period, and among those who continued 28% were non-adherent. Younger women were at high risk of non-adherence being 50% more likely to discontinue therapy and 40% more likely to be non-adherent (P < 001). Among patients taking AIs the musculoskeletal toxicities are the main reason for treatment discontinuation/nonadherence [147–149]. Predictive factors of these adverse ef-

fects have been studied, but have not been consistent among studies. A retrospective exploratory analysis from the ATAC trial has shown that previous hormone replacement therapy, previous CT and obesity were risk factors for the development of joint symptoms. A recent exploratory analysis from a prospective study, the Exemestane and Letrozole Pharmacogenetics (ELPh) clinical trial [150], found that younger age and prior taxane-based CT were associated with a greater likelihood of treatment discontinuation, but prior tamoxifen therapy, prior hormone replacement therapy and body mass index were not predictors. One third of patients prematurely discontinued adjuvant AI therapy in this study, but it was also seen than more than one third of patients who switched drugs tolerated the second AI, confirming previous results [151]. There is no evidence to demonstrate differences in efficacy and toxicity among AIs. Anastrazol has shown efficacy similar to that of letrozol in the MA.27 trial [152]. The results from the FACE trial comparing two non-steroidal AIs, letrozole and anastrozole, are awaited. The main predictors of response to hormonal treatment are oestrogen and progesterone receptors [114]. There is no

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evidence to support HER2 status as predictive of different responses to tamoxifen or AIs [129,153]. New genomic tools such as Oncotype DX and PAM50 [30,154] have been predictive of tamoxifen treatment, but their use in clinic has been mainly as a prognostic tool. Recently an exploratory analysis from the BIG 1-98 trial [155] of 2599 patients treated with tamoxifen monotherapy or letrozol monotherapy, with a 12-year follow-up, showed a significant interaction effect between histology subtype and degree of benefit to letrozole over tamoxifen, with greater benefit being seen with letrozol in women with lobular carcinomas compared with invasive ductal carcinomas. Although these data need further validation, it restores confidence in the use of AI in high-risk lobular tumours.

6. What is the optimal adjuvant anti-HER2 treatment? For patients with HER2+ early BC the use of trastuzumab and CT is well established and evaluated in six adjuvant trastuzumab randomised clinical trials (Table 5) involving more than 13,000 women: the Herceptin Adjuvant trial (HERA) [156], the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and the North Central Cancer Treatment Group (NCCTG) N9831 trial [157], the Breast Cancer International Research Group (BCIRG) 006 trial [79], the Finland Herceptin trial (FinHER) [158] and the Protocol Adjuvant dans le Cancer du Sein (PACS-04) trial [159], and in a 2012 meta-analysis [160]. All trials except PACS-04 yielded an improved DFS (HR between 0.6 and 0.77) and OS (HR between 0.55 and 0.77) with the administration of trastuzumab (Table 5). Cardiac toxicity data from these trials indicate that the rate is higher when anthracyclines are used and with concurrent regimens. Nevertheless, the rates are always low and clinically acceptable. The 2012 meta-analysis of eight studies, involving 11,991 patients, assessed the benefits of adding trastuzumab to adjuvant CT in patients with HER2+ BC [160]. The inclusion of trastuzumab resulted in an improvement in DFS with an HR = 0.60 (95%CI 0.50–0.71), regardless of trastuzumab treatment duration or administration schedule (i.e. concurrently or sequentially with CT) and an improvement in OS with an HR = 0.66 (95%CI 0.57–0.77).

6.1.

Timing of trastuzumab initiation

The decision about whether trastuzumab should be administered concurrently or sequentially after the completion of adjuvant CT as been addressed directly in the N9831 trial. The second planned interim analysis, with a median followup of 6 years, indicates that although trastuzumab added sequentially to CT improves DFS, there is a strong trend towards a better outcome with concurrent trastuzumab relative to sequential administration [161]. In the 2012 meta-analysis the benefit in OS was associated with concurrent administration [HR 0.64 (95%CI 0.53–0.76)] but not with sequential treatment of CT followed by singleagent trastuzumab [HR 0.85 (95%CI 0.43–1.67)] [160]. BCIRG006 also support the use of trastuzumab administered concurrently with CT in the adjuvant setting [79].

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6.2.

Duration of trastuzumab treatment

One year of trastuzumab is the standard of care in adjuvant therapy. In the HERA trial a comparison between 1 and 2 years of adjuvant trastuzumab after CT concluded that 2 years of treatment was not better than 1 year [162]. The PHARE trial recruited over 3380 HER2+ patients and randomly assigned them to receive either 6 months or 1 year of adjuvant trastuzumab. The trial results were reported as unable to prove the non-inferiority hypothesis of 6 months versus 1 year of adjuvant trastuzumab [163]. In the 2012 meta-analysis trastuzumab administered for 12 months was associated with an improvement in OS [HR 0.67 (95%CI 0.57–0.80)]; although trastuzumab treatment for 66 months also showed a trend towards an improvement in OS, it did not reach statistical significance [HR 0.55 (95%CI 0.27–1.11)] [160]. Several trials are still ongoing evaluating the optimal duration and regimen of adjuvant trastuzumab; these might lead to a different conclusion in the future. The relative benefit of 6 months versus 1 year of trastuzumab is being evaluated in the PERSEPHONE trial (which also evaluates sequential versus concurrent trastuzumab) and the HELLENIC trial (using only concurrent therapy). The SHORT-HER and SOLD trials are evaluating 9 weeks versus 12 months of trastuzumab given concomitantly with a taxane, similar to the FinHER trial.

7.

Conclusions and future perspectives

(Neo)adjuvant systemic therapy has dramatically changed the natural history of EBC. Together with screening and early detection, it is responsible for the 30% decrease in mortality observed since the 1990s. The stronger effects are seen with biologically targeted agents such as endocrine and anti-HER2 therapies. Similar advances are still lacking for the heterogeneous groups of triple-negative EBC. Prognostication has been greatly improved in the last decade, but advances in prediction have been only minimal and remain a research priority. New technologies and a better knowledge of the biology of the different subtypes of BC, as well as an in-depth understanding of the mechanism of cancer resistance, will hopefully enable us to achieve a true individualised/personalised medicine in the near future

Conflict of interest statement The author has a potential conflict of interest with the following companies: Eisai, Roche, GSK, Celgene, AstraZeneca, Novartis, GE Oncology, Merck-Sharp, Merus BV, Genentech and Pfizer. R E F E R E N C E S

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strategies for management. Oncology (Williston Park) 2008;22(12):1401–8. Sestak I, Cuzick J, Sapunar F, Eastell R, Forbes JF, Bianco AR, et al. Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis. Lancet Oncol 2008;9(9):866–72. Henry NL, Azzouz F, Desta Z, Li L, Nguyen AT, Lemler S, et al. Predictors of aromatase inhibitor discontinuation as a result of treatment-emergent symptoms in early-stage breast cancer. J Clin Oncol 2012;30(9):936–42. Briot K, Tubiana-Hulin M, Bastit L, Kloos I, Roux C. Effect of a switch of aromatase inhibitors on musculoskeletal symptoms in postmenopausal women with hormonereceptor-positive breast cancer: the ATOLL (articular tolerance of letrozole) study. Breast Cancer Res Treat 2010;120(1):127–34. Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, et al. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27 – a randomized controlled phase III trial. J Clin Oncol 2013;31(11):1398–404. Berry DA, Muss HB, Thor AD, Dressler L, Liu ET, Broadwater G, et al. HER-2/neu and p53 expression versus tamoxifen resistance in estrogen receptor-positive, node-positive breast cancer. J Clin Oncol 2000;18(20):3471–9. Chia SK, Bramwell VH, Tu D, Shepherd LE, Jiang S, Vickery T, et al. A 50-gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant tamoxifen. Clin Cancer Res 2012;18(16):4465–72. Metzger O G-H, Mallon E, Viale G et al. Relative effectiveness of letrozole compared with tamoxifen for patients with lobular carcinoma in the BIG 1–98 trial. Cancer Res 2012 [Abstract S1–1]. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):1659–72.

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[157] E Romond VS J-HJ, GW Sledge, Jr., CE Geyer, Jr., S Martino, P Rastogi, J Gralow, SM Swain, E Winer, G Colon-Otero, C Hudis, S Paik, N Davidson, EP Mamounas, JA Zujewski, N Wolmark, EA Perez, and National Surgical Adjuvant Breast and Bowel Project (NSABP) Operations and Biostatistical Centers. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: Final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831. Cancer Res 2012;72(24):Suppl. 3. [158] Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol 2009;27(34):5685–92. [159] Spielmann M, Roche H, Delozier T, Canon JL, Romieu G, Bourgeois H, et al. Trastuzumab for patients with axillarynode-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol 2009;27(36):6129–34. [160] Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev 2012;4:CD006243. [161] Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, et al. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol 2011;29(34):4491–7. [162] Gelber RD GA, Piccart M, et al. HERA Trial: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. 2012 ESMO Congress. 2012 Presented October 1, 2012 [Abstract LBA6]. [163] Pivot X RG, Bonnefori H, et al. PHARE trial results of subset analysis comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer 2012 ESMO Congress. 2012 Presented October 1, 2012 [Abstract LBA5].

The role of the pathologist in the decision-making process Angelo Paolo Dei Tos

*

General Hospital of Treviso, Department of Oncology and Pathology, Treviso, Italy

1.

Introduction

During the last two decades the pathological classification of breast carcinoma has evolved rapidly. Starting from the pure assessment of conventional morphology, it has gradually been integrated with immunophenotypic evaluation of the hormone receptor, HER2, and Ki67 status. In addition, molecular genetic testing (mostly by fluorescence in situ hybridisation, FISH) for Her2 immunohistochemically ‘equivocal’ cases has become a standard. Pathological evaluation of breast specimens has shifted rapidly from a mere diagnostic process, aimed at establishing the biological potential of a breast ‘lump’, to a far more complex integration of diagnostic, prognostic and predictive parameters. The current landscape has been further complicated by the relatively recent introduction of a ‘molecular’ classification of breast cancer [1]. Since then pathologists and clinicians have struggled in the attempt to translate (or maybe to force) the classic morphological approach into a molecularly based scheme (Table 1). Whatever the approach, the role played by the pathologist in the clinical decision-making process has never been so central. Establishing the correct diagnosis, as well as accurately evaluating key prognostic/predictive biomarkers, represent the core of the breast cancer pathology report. Even acknowledging the current complexity of personalised treatments, it is broadly accepted that the information mandatory for inclusion in the pathology report represents a milestone for optimal therapeutic planning.

2.

Pathological diagnosis

The pathological diagnosis of breast carcinoma still represents the key step. Before considering the complex integration of predictive and prognostic markers, it should not be overlooked that the diagnosis of breast cancer is not always straightforward. The presence, within the breast cancer multidisciplinary team, of a skilled breast pathologist represents a fundamental prerequisite in order to achieve optimal therapeutic planning.

The World Health Organisation (WHO) has recently updated its breast cancer classification, separating invasive breast carcinoma into two broad categories: invasive carcinoma of no special type (formerly known as invasive ductal carcinoma) and special subtypes (Table 2). The recognition of special subtypes is relevant as distinct morphologies often correlate with distinct clinical outcomes [2]. Once the correct diagnosis of invasive carcinoma is made, pathologists are asked to provide a set of morphological parameters representing important clues to prognostic stratifications. These include the size of the lesion, the presence of lymphatic and blood vessel invasion, the status of lymph nodes and the histological grading (Table 3). The currently adopted grading system is that devised by Elston and Ellis, and represents a powerful prognostic tool that represents a key factor in clinical decision-making [3]. The so-called Nottingham system is based on the evaluation of differentiation (as expressed by the amount of tubule formation), nuclear pleomorphism (by comparing neoplastic cell nuclei with adjacent normal breast epithelial cells) and mitotic activity (as expressed by number of mitoses counted per 10 high-power fields). Of course the dimension of a ‘high-power field’ depends on the size of the microscope. The WHO, in its most recent classification, has therefore provided a conversion table aimed at minimising inter-observer variability [2]. As shown, pathological evaluation of haematoxylin-andeosin-stained slides still represents the cornerstone of breast cancer diagnosis. Even though molecular testing is playing an increasingly key role in several fields of cancer, it is extremely important that morphological expertise is not lost, and that educational efforts are supported in order to maintain diagnostic skills to the highest possible standard.

3.

Evaluation of predictive/prognostic markers

The three main biomarkers used in the routine clinical management of invasive breast carcinoma are represented by the oestrogen receptor (ER), progesterone receptor (PR) and HER2. More recently, the evaluation of the Ki67 labelling index has

* Tel.: +38 348 5193527. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright  2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.027

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Table 1 – Molecular classification of breast cancer. Subtype

Clinico-pathological definition

Luminal A

ER- and/or PR-positive HER2-negative Ki67 low (75 1 10–75 2 Nuclear pleomorphism Absent 1 Moderate 2 Mitotic count (depends on microscope field area) Low 1 Intermediate 2 High 3

specifically correlates gene expression with key clinical parameters such as overall or disease-free survival as well as response to a given therapy. The unsupervised hierarchical cluster analysis of breast carcinoma has led to a broad division into ER+ and ER cases [18,19]. If the set of genes expressed by the two categories is examined closely, ER+ cases are linked to breast luminal cells, whereas ER cases are associated with myoepithelial cells. The next step is the correlation of these subgroups with clinical outcomes. This approach has led to the definition of the entities (intrinsic subtypes) listed in Table 1: namely types luminal A and B, HER2 and basal-like [1,20]. The attempt to correlate gene expression profiles with clinical outcome has generated several gene signatures. The most popular is represented by a 70-gene signature that may determine prognosis in stage-1 or -2 node-negative patients affected by breast carcinomas smaller than 5 cm. The 70-gene signature separates patients into two groups with good and poor prognoses, and appears to work as an independent predictor of metastatic spread [1]. The 70-gene signature has been popularised with the commercial label Mammaprint which has been cleared by the FDA as an in vitro diagnostic multivariate index assay. An alternative approach is represented by the 21-gene recurrence score [21]. This is a qRT-PCR-based signature commercially named Oncotype DX, that predicts the likelihood of recurrence at 10 years for ER-positive, lymph-node-negative patients. The test provides a continuous recurrence score (RS) and risk category: low (RS < 18), intermediate (RS 18–30) and high (RS > 30). The 21-gene recurrence score apparently may also correlate with benefit from chemotherapy in ER-positive breast cancer patients [21]. The clinical utility of gene expression profiling in breast cancer has generated a lively and still ongoing debate. Even if there is a strong pressure (particularly in the US, United States) towards a broader use of such approaches, their potential benefit seems until now to be restricted to a minority of breast cancer patients. Nonetheless, also in consideration of the rapid evolution (and cost reduction) of molecular genetic techniques, it has to be expected that molecular assays will be implemented increasingly in clinical practice.

5.

Conclusions

Pathological evaluation of breast cancer specimens plays a key role in planning the best therapeutic options. In addition

1 1 ( 2 0 1 3 ) 2 3 –2 6

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to accurate diagnosis of malignancy and cancer subtype, pathologists are central in helping clinicians in the selection of patients for both endocrine therapy as well as for antiHer2 targeted approaches. Precise evaluation of breast cancer biomarkers still represents a key issue not yet entirely resolved, and it has been shown to impact on clinical decision-making as well as on patient outcome. It is vital that pathology laboratories systematically implement External Quality Control policies aimed at achieving and maintaining the highest diagnostic standard. The rapid evolution of molecular techniques has in part changed the landscape of breast cancer prognostic biomarkers. The advent of genomic signatures certainly represents a step forward, but their clinical utility is being still debated; complete agreement regarding their clinical as well as their cost-effectiveness is still to be achieved.

Conflict of interest statement The authors have no conflict of interest relating to this article.

R E F E R E N C E S

[1] Van de Vijver MJ, He YD, Van’t Veer LJ, et al. A geneexpression signature as a predictor of survival in breast cancer. N Engl J Med 2002;347:1999–2009. [2] Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ, editors. WHO classification of tumours of the breast. Lyon: IARC; 2012. [3] Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histologic grade in breast cancer: experience from a large study with long term follow-up. J Natl Cancer Inst 2011;103:1656–64. [4] Dowsett M, Nielsen TO, A’Hern R, et al. Assessment of Ki67 in breast cancer: recommendation from the international Ki67 in breast cancer working group. J Natl Cancer Inst 2011;103:1656–64. [5] Harvey JM, Clark GM, Osborne CK, Allred Dc. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999;17:1474–81. [6] Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365: 1687–717. [7] Schiff R, Osborne CK, Fuqua SAW. Clinical aspects of estrogen and progesterone receptors. In: Harris JR, Lippman ME, Morrow M, Osbourne CK, editors. Diseases of the breast. Wolfers Kluver Lippincott William and Wilkins; 2010. p. 408–30. [8] Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010;28:2784–95. [9] Clark RB. Steroid receptors and proliferation in the human breast. Steroids 2003;68:789–94. [10] Mohsin SK, Weiss H, Havighurst T, et al. Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: a validation study. Mod Pathol 2004;17:1545–54.

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[11] Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone to adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 2003;21:1973–9. [12] Allred DC. Issues and updates: evaluating estrogen receptoralpha, progesterone receptor, and HER2 in breast cancer. Mod Pathol 2010;23:S52–9. [13] Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–82. [14] Perez EA, Reinholz MM, Hillman DW, et al. HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial. J Clin Oncol 2010;28:4307–15. [15] Press MF, Finn RS, Cameron D, et al. HER2 gene amplification, Her2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res 2008;14:7861–70. [16] Wolff AC, Hammnond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American

1 1 (2 0 13 ) 2 3–26

[17]

[18] [19]

[20]

[21]

Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007;25:118–45. Perez EA, Press MF, Dueck AC, et al. Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005). Breast Cancer Res Treat 2013;138:99–108. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of breast cancer. Nature 2000;406:747–52. Van’t Veer LJ, Dai H, Van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:718–9. Perou CM, Parker SJ, Prat A, Ellis MJ, Bernard PS. Clinical implementation of the intrinsic subtype of breast cancer. Lancet Oncol 2010;11:718–9. Paik S, Shak S, Tang G, et al. A multigene essay to predict recurrence of tamoxifene-treated node-negative breast cancer. N Engl J Med 2004;351:2817–26.

Optimal approach in early breast cancer: Radiation therapy Philip Poortmans

*

Institute Verbeeten, Department of Radiation Oncology, Tilburg, The Netherlands

A R T I C L E I N F O

Radiation therapy significantly reduces by at least 70% the relative risk of local and regional recurrences for breast cancer after surgery. A positive influence on overall survival has been clearly demonstrated, especially for patients with a high absolute risk for locoregional recurrences. However, this is partially counterbalanced by late toxicity (dependent upon the radiation dose) especially to cardiac structures. Apart from this toxicity, a clear influence of radiation-therapy-related factors on functional and cosmetic outcome has also been demonstrated. Over time, technical improvements have led to a marked reduction in dose to the neighbouring organs, with a consequent drop in acute and late toxicity. This has also allowed the introduction of shorter radiation schedules, lowering the burden of treatment to the patient and the hospital. Several tools, techniques and guidelines have been developed to optimise the balance between the desired reduction in recurrence rates and side effects. The multidisciplinary team should discuss all available treatment options for every individual breast cancer patient. Individualisation of the selection of the optimal combination of treatments, depending on patient and tumour-related factors, is of utmost importance. Apart from direct tumour-related outcomes, cosmesis and potential side effects have to be taken into account. Counselling should include known risk factors for survival and complications, including comorbidity. Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved.

1.

Introduction

Radiation therapy (RT) forms an integral component of the management of early-stage breast cancer. Over the years, significant progress – accelerating over time – has resulted from our growing knowledge of the biology and the natural behaviour of breast cancer as well as from technical improvements in RT. While initially research focused on optimising locoregional disease control by combining surgery with RT, the introduction of breast-conserving therapy (BCT) initiated a period of research aimed at lowering the burden of treatment [1,2]. At the same time, adjuvant systemic treatment became widely used, resulting in a reduced risk of metastases and thereby improving overall survival. The interaction between the benefits from both locoregional and systemic treatments opened the way to further

improving the clinical outcome for breast cancer patients in terms of survival as well as quality of life. The 21st century started with a number of developments, including fine-tuning of the indications for RT for each individual target volume (intact breast, post-mastectomy chest wall, axillary, internal mammary and supraclavicular lymph nodes) depending on the clinicopathological features of an individual patient’s disease, as well as hypofractionation and accelerated partial breast irradiation.

2. Prognostic factors influencing locoregional treatment Several prognostic factors determine the risk of recurrence at local, regional and distant sites. On the basis of this, recom-

* Tel.: +31 (0)135947765. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.028

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mendations for both local and systemic treatments for patients with breast cancer are defined. Factors influencing the risk of recurrence include tumour size, tumour grade, margin status, lymph-node involvement, oestrogen and progesterone receptor status, HER-2/neu status and patient age. Whereas the relative benefit of locoregional and systemic therapy remains largely independent of these factors, they greatly determine the absolute benefit that can be expected. For systemic therapy they also determine the selection of its type (endocrine therapy, chemotherapy, trastuzumab, or a combination of these). Age may also influence treatment recommendations as it helps to predict the relative risk for death related to cancer compared to death from other causes. In general, treatment tolerability, especially for chemotherapy, tends to decrease with increasing age. Patients who are BRCA1 or BRCA2 mutation carriers should receive extensive counselling to discuss the possible approaches, including BCT and mastectomy, and even including prophylactic contralateral mastectomy given their increased risk of developing a second primary breast cancer in either breast in the future [3,4].

3.

Breast conserving therapy

3.1.

Lumpectomy with or without radiation therapy

It is well recognised that up to 80% of patients with invasive breast cancer may benefit from BCT, which offers rates of disease control and survival similar to those of mastectomy. This was confirmed by the meta-analyses of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) [5]. Candidates for BCT include patients with unicentric disease that can be removed with negative margins and with acceptable cosmetic results. The size of an invasive breast cancer, in relation to overall breast size, in a patient considering BCT will determine whether neoadjuvant chemotherapy or endocrine therapy is required to reduce the size of the primary tumour prior to definitive surgery. Patients with multicentric tumours and inflammatory breast cancer are not considered candidates for BCT. Patients with multifocal tumours within a single quadrant of the breast – which can be removed in a single segmental resection with clear margins and a cosmetically acceptable result – may be considered candidates for segmental resection followed by whole-breast RT. Oncoplastic surgical techniques that are becoming more widely used clearly extend the range of possibilities for BCT with acceptable cosmetic outcomes in patients that were offered mastectomy in the past. Excision alone without RT may occasionally be considered for patients at low risk of recurrence. In these cases, it is recommended that the negative margins be wide (P10 mm). For instance, patients older than 70 years with oestrogen-receptor-positive T1 primary tumours may choose to forgo whole breast RT, if they accept receiving 5 years of endocrine therapy, because of their lower risk of local recurrence in the breast. However, whole breast irradiation in this setting does reduce the risk of local recurrence by at least two thirds [6]. Moreover, adjuvant hormonal treatment – which also carries side effects – can be avoided if RT is given.

1 1 (2 0 13 ) 2 7–36

3.2.

Boost

The purpose of the boost is to deliver additional radiation to the area at the highest risk of harbouring microscopic residual disease: namely, the primary tumour bed and immediately surrounding breast parenchyma. Multiple studies have shown that this area has the highest risk of recurrence in the breast [7,8]. While the EORTC trial 10801 comparing mastectomy and BCT demonstrated equivalent overall survival rates for up to 20 years after treatment, a significant difference in local control was seen between the participating centres, and the high boost dose of 25 Gy that was used resulted in a significant proportion of the patients with severe fibrosis and a poor cosmetic outcome [9]. The next EORTC ‘‘boost’’ trial 22881/10882 paid special attention to quality assurance, fibrosis and cosmetic scoring. The boost dose was lowered from 25 Gy to 16 Gy, which was randomised against no boost at all. This trial and two other prospective randomised trials showed that delivering a boost dose to the tumour bed after whole breast irradiation significantly reduces the local recurrence rate [7,10,11]. Young age appears to be the most significant independent patient factor related to local recurrence. The absolute effect of the boost – reducing the local recurrence rate relatively by 41% overall – was much more marked for younger patients (Fig. 1) [7,12]. The cosmetic results were scored as excellent to good in 86% of patients receiving no boost and in 71% of patients receiving a boost. Apart from the boost dose, other predictors for cosmetic outcome included whole breast dose and megavolt energy, type of boost, energy of electrons, and use of adjuvant chemotherapy or hormonal therapy [13]. An inhomogeneous dose distribution of whole breast RT negatively influenced the risk for developing fibrosis, similar to the findings of Donovan and colleagues [14]. Based on this trial, nomograms have been developed to predict in individual patients the impact of a boost dose of 16 Gy on the rate of ipsilateral breast relapse (http://research.nki.nl/ibr) and fibrosis [13,15]. To evaluate the need for a further increase in the boost dose from 16 Gy to 26 Gy for patients up to 50 years of age, the ‘‘Young Boost Trial’’ (NCT00212121) was run in The Netherlands, Germany and France between 2004 and 2011. Early analysis of the results, without splitting up for the randomisation arm, shows that the estimated local recurrence rate remains far below the results obtained in trials, despite the much younger age in the population investigated.

3.3.

Accelerated partial breast irradiation

As previously mentioned, after lumpectomy with surgical axillary staging, the standard of care is whole breast irradiation with or without a boost dose. However, accelerated partial breast irradiation (APBI) is rapidly emerging as a treatment option for early-stage invasive breast cancer in certain clinical scenarios. It may be considered in women who are P50 years of age, with tumours that are pathologically 3 cm or smaller, and node-negative. Ideally, these patients should be treated in the framework of clinical trials because of the more limited long-term data for APBI compared with those for whole breast

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Fig. 1 – Cumulative incidence of breast cancer recurrence according to age group. Reproduced with permission from [7].

irradiation [16–18]. It is expected that in the near future, after completion of the prospective randomised clinical trials comparing APBI with standard whole breast irradiation, a precise definition of the place of APBI will become available.

3.4.

Young patients

It is important to see the clear decrease in local recurrence rates over time in the EORTC 10801, EORTC 22881–10882 and Young Boost trials (Fig. 2) [19]. The explanation of this continuous improvement is multifactorial and includes technical and diagnostic factors and the increasing use of adjuvant systemic treatment. It is well established that chemotherapy and hormonal treatment reduce local recurrence rates by about 35–50%. Indeed, according to the consensus at the time, virtually no patient who participated in the EORTC 10801 trial, and only 31% of the patients participating in the EORTC 22881– 10882 trial, received adjuvant systemic treatment, while in the Young Boost trial nearly all patients received systemic treatment, often combined chemotherapy and hormonal treatment [12]. Therefore, results from the past after BCT in young patients should not be considered as a contraindication for offering this treatment today to patients 10% of patients [1]. Another drawback of EUS compared to cross-sectional imaging techniques is that it is highly operator-dependent and requires a learning curve before optimal diagnostic performance can be obtained [2]. A potential benefit of EUS compared to CT and MRI is that it allows for tissue biopsies within one single examination, so that histopathological confirmation can immediately be obtained.

2.2.

Computed tomography (CT)

Multislice CT (MSCT) is often considered the modality of first choice for the distant staging of colorectal cancer (e.g. the detection of metastatic spread to the liver and/or lungs). Although it has been proposed by some authors that simultaneous staging of the rectal tumour using CT as a ‘one-stop-shop’ imaging tool may be beneficial, there are several drawbacks to the use of CT for assessing the local tumour status. First of all, the soft tissue contrast of CT is limited, making it more difficult to distinguish between tumours limited to the bowel wall and those which have penetrated the wall. For the assessment of an involved mesorectal fascia, MSCT is reported to have moderate to poor accuracy (54–66%). Interestingly, CT can reach fairly good diagnostic performance for assessing the MRF in tumours that are located in the mid–high rectum with reported positive predictive values (PPVs) and negative predictive values (NPVs) of 86% and 94%, respectively. It is particularly in low rectal tumours where the limited soft tissue contrast of CT hampers a reliable differentiation between the tumour and surrounding structures, resulting in a PPV and NPV of only 53% and 73% in assessing an involved MRF [3]. For the evaluation of lymph nodes, CT experiences the same difficulties as MRI and EUS, which are discussed in detail below.

* Corresponding author. E-mail addresses: [email protected] (D.M.J. Lambregts), [email protected] (R.G.H. Beets-Tan). 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.031

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2.3.

Positron emission tomography (PET)

PET allows for the detection of metabolically active tissues (e.g. malignant tumours) using tumour-tracing radiopharmaceuticals, of which in oncology the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) is the most widely adopted. FDG-PET can be performed in combination with computed tomography (CT). This hybrid PET–CT allows for a simultaneous assessment of tumour morphology together with the functional information from PET. The role of PET(–CT) for the primary staging of colorectal cancer is limited. Because PET is known to miss small metastatic lesions in the liver – due to its limited spatial resolution – it is not recommended as the staging modality of first choice. However, in patients with known liver metastases scheduled for liver surgery, PET(–CT) is very accurate in excluding the presence of extrahepatic lesions such as lymph-node and bone metastases. In this context, the use of PET can significantly decrease the number of futile laparotomies [4]. A second clinical application of PET(–CT) is the detection of recurrent tumours in patients with a suspected recurrence after primary surgical treatment for colorectal cancer. In this setting PET has advantages over CT, MRI and EUS in differentiating between recurrent tumour and postoperative scar tissue. Recently there is a growing interest in the use of PET(–CT) as a tool to predict treatment response in patients with locally advanced rectal cancer treated with chemoradiotherapy. Assessment of the decrease in the standardised uptake value (SUV) during chemoradiation has been reported by several authors to be a strong indicator for therapeutic efficacy [5]. Although at present these findings will not yet impact the treatment plan, in the future early response prediction using functional imaging methods such as PET may be of great clinical value as this may allow for early treatment adaptations to enhance the chance of a good therapeutic response.

2.4.

Magnetic resonance imaging (MRI)

MRI using modern phased-array external coils offers the advantages of an excellent soft tissue contrast, high spatial resolution and a large field of view. This makes MRI an invaluable technique for detailed morphological information on both the tumour and its extension into the surrounding mesorectal compartment and neighbouring organs. MRI is the recommended imaging method for staging and restaging of rectal cancer in most European countries. The following sections will elaborate on aspects of MRI relevant for rectal cancer imaging, including the optimal MR protocol.

3.

MRI protocol for the staging of rectal cancer

3.1.

Patient preparation

MRI using phased array external coils has become the standard technique for state-of-the-art imaging of rectal cancer. MRI using an endorectal coil, although similar in performance to EUS for the assessment of superficial (T1 and T2) tumours, has not gained worldwide acceptance. First, endorectal MRI is more cumbersome in application and less patient-friendly

1 1 ( 2 0 1 3 ) 3 8 –4 4

39

than EUS and does not allow for simultaneous tumour biopsies, which is an added advantage of EUS. Furthermore, coil positioning for endorectal MRI can be very difficult, particularly in high and/or stenosing tumours. For phased array MRI routine use of spasmolytics or bowel preparation is not required. Nevertheless, occasional use of spasmolytics may be helpful when severe bowel movement artefacts are already visible on the (sagittal) planning scan, particularly in patients presenting with tumours situated high in the rectum and thus nearer to adjacent small bowel loops. Use of endorectal contrast or filling (for example using ultrasonography gel) is not recommended as part of standard clinical routine. The main argument for applying endorectal filling is to allow a more confident assessment of the exact tumour location within the lumen, particularly in smaller-sized tumours [6]. However, given the fact that information on the tumour location is given during endoscopy, the use of intraluminal filling does not outweigh its potential disadvantages. Apart from the patient burden, the introduction of endorectal contrast causes stretching of the rectal wall which in turn compresses the mesorectal compartment. Hence, rectal distension may hamper the assessment of lymph nodes in the mesorectal compartment and can also result in overestimation of tumour invasion of the mesorectal fascia [7], which are in fact two of the principal important factors that need to be evaluated with MRI (see also section below on assessing risk factors for local recurrence).

3.2.

Imaging sequences

A standard rectal MR protocol should consists of multiplanar T2-weighted Fast Spin Echo (T2W FSE) sequences, since these offer an optimal soft tissue contrast between the tumour, the mesorectal fat and the mesorectal fascia surrounding the mesorectal compartment. The optimal slice thickness of the T2W sequences ranges between 1 and 3 mm and should not exceed 5 mm. A sagittal T2W sequence should be first obtained in order to localise the tumour and allow for proper angulation of the axial and coronal planes. It is of the utmost importance that the axial and coronal planes are angled exactly perpendicular and parallel to the longitudinal tumour axis (as identified on the sagittal scan) so that the relationship of the tumour with the surrounding organs and structures can reliably be assessed. In very low rectal tumours the coronal sequences should be angled parallel to the anal canal to establish the relation of the tumour to the pelvic floor and anal sphincter musculature. There is no solid evidence yet for the routine use of additional sequences other than T2W sequences in three planes. Fat-suppression sequences are not recommended since they do not allow a proper appreciation of the mesorectal fascia. A (non-enhanced) T1-weighted sequence may be useful for the evaluation of coincidental findings in other pelvic organs, but is not required for the staging of rectal cancer. There is no solid indication for the administration of intravenous contrast agents. Gadolinium contrast was shown not to be beneficial for T-stage and CRM evaluation [8]. Although experimental studies have investigated the use of dynamic contrast-enhanced MRI and lymph-node-specific contrasts, at the time of writing these techniques are not yet recommended for daily clinical

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practice [9–11]. Similarly, diffusion weighted imaging (DWI) sequences have so far been obtained mainly in research protocol settings, although there is growing evidence that the addition of DWI may be valuable, especially in the restaging setting after chemoradiation to re-evaluate the primary tumour (see also section on diffusion-weighted MRI below).

4. Assessing the recurrence using MRI

risk

factors

for

local

There are four main risk factors for developing a local recurrence, which are used to determine treatment planning: (1) the tumour height (low, middle or upper third of the rectum), (2) the local extent of the tumour (T-stage), (3) involvement of the mesorectal fascia and (4) nodal involvement (N-stage).

4.1.

Tumour height

Tumour height is an important parameter as low rectal tumours (e.g. within the first 5 cm above the anal verge) are known to have a worse prognosis than tumours situated higher in the rectum. As a result of the distal tapering of the mesorectum and consequent decrease of the thickness of the fat plane surrounding the rectum, low tumours have a relatively close relationship with the mesorectal fascia, the pelvic floor muscles and the anterior pelvic organs (prostate/seminal vesicles in men and vagina/uterus in women) and have a higher risk of invasion. Although the tumour height can be accurately measured on MRI (often using the anorectal junction as a reference point) the surgeon is generally already aware of the tumour location from his endoscopic assessment, so often this is not one of the strong arguments to perform imaging. In the United States, the location of the tumour in relation to the peritoneal reflection is often used as an additional landmark to determine whether a patient requires neoadjuvant treatment (if the tumour is below the peritoneal reflection) or not (if the tumour is above the peritoneal reflection). The level of the tumour in relation to the peritoneal reflection can be accurately assessed using MRI [12].

4.2.

Tumour (T-)stage

The overall reported accuracy for T-stage prediction with phased array MRI varies between 67% and 83% [13]. The main strength of MRI is the evaluation of large T3 tumours that penetrate the muscular rectal wall and T4 tumours invading adjacent organs, for which MRI has been reported to achieve sensitivities and specificities of 74% and 76% (in T3 tumours) and 82% and 96% (in T4 tumours), respectively [14]. MRI, however, is known to have difficulties in differentiating between superficial T1 and T2 tumours. As opposed to EUS, with MRI it is not possible to separately appreciate all three layers of the rectal wall. The submucosal layer of the rectal wall is not visualised on phased-array MRI (except when there is oedema). Hence, differentiation between a T1 tumour limited to the submucosa and a T2 tumour penetrating the muscularis propria is not feasible. Consequently, EUS remains the cornerstone technique for the selection of superficial T1 tumours that can be considered for local excision. Another limitation

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of MRI (as well as EUS) is the differentiation between T2 and borderline T3 tumours. Desmoplastic strands into the mesorectal fat in a T2 tumour without actual tumour infiltration cannot be discriminated from desmoplastic reactions containing tumour nests indicating a T3 tumour. In practice, this results in the over-staging of a considerable number (up to 40%) of T2 tumours because radiologists tend to err ‘on the safe side’ rather than risk under-staging [15,16]. Only when the bowel wall on T2-weighted MR images is visualised as a completely intact hypointense line around the tumour does this indicate an intact muscular bowel layer, which can be used as a reliable predictor for the tumour being limited to the bowel wall (T1–2) with a PPV of 86–91% [17].

4.3.

The mesorectal fascia (MRF)

Preoperative knowledge of tumour involvement of the MRF is critical in order to determine whether it will be possible to obtain a complete resection of the tumour. Assessment of the MRF is only relevant in the case of a T3 or T4 tumour. When it is established that the tumour is surrounded by an intact bowel wall (indicating a T1–2 tumour) the MRF will never be involved [13]. In the case of a PT3 tumour, the relation between the tumour and the MRF should be evaluated (i.e. the circumferential resection margin at TME). When the tumour invades the MRF or extends within a margin of 90% for MRI in predicting tumour involvement of the MRF [18]. In a meta-analysis of seven individual reports (including the MERCURY cohort) sensitivities and specificities for MRI ranged between 60% and 88% and between 73% and 100% respectively [19].

4.4.

Lymph nodes and extramural venous invasion (EMVI)

In addition to MRF involvement, lymph-node status comprises one of the main factors that determine the necessity for the addition of neoadjuvant radiotherapy and/or chemotherapy. Unfortunately, so far MRI, EUS and CT have not proved to be sufficiently accurate to determine the nodal status. The main problem is that imaging relies on nodal size (i.e. short axis diameter) as the main criterion to discriminate between benign and metastatic nodes. In rectal cancer in particular it is known that size is not a reliable predictor because metastases frequently occur in small (1 cm. In practice, the chosen size threshold depends mainly on the desired balance between sensitivity and specificity, more often favouring the former. Two meta-analyses that analysed the pooled data from nodal imaging studies using size criteria on EUS, CT or MRI showed similarly poor sensitivities and specificities in the range of 55–78% [14,19]. Some authors have shown that the use of morphological criteria in addition to size can improve the diagnostic performance of imaging in assessing the lymph nodes with reported sensitivities of 36–85% and specificities of 95–100% [21,22]. Nodes with a sharply delineated border and homogeneous signal

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intensity tend to be benign. In contrast, nodes with an irregular border and heterogeneous signal pattern are more likely to be involved. These criteria have not, however, been widely implemented into clinical practice, probably partly because these features are quite difficult to evaluate in very small nodes (62–3 mm). Apart from nodes within the lower and mid mesorectal compartment, a report on rectal cancer should also mention any suspicious nodes that are located high in the mesorectum, along the superior rectal vessels, as well as outside the mesorectum below the internal iliac bifurcation at the root of the medial rectal vessels (the lateral nodes), as involvement of these nodes harbours a higher risk for distant and local recurrence and will need to be included in the radiation field and/or removed with surgery. Extramural venous (or vascular) invasion (EMVI) is the presence of tumour invasion in the veins in the vicinity of the tumour. EMVI, as established at histology, is known to be associated with an increased risk of local and distant recurrence and an impaired overall survival [23]. As such, EMVI is considered an important prognostic marker at histopathology. It has been shown that the presence of EMVI can be assessed on MRI based on the presence of tumoural signal intensity within vessels surrounding the rectum, or the presence of a nodular expansion or irregular vessel contour as criteria [24]. It has furthermore been suggested that the presence of EMVI may be related to the presence of nodular disease, since lymphatic vessels run parallel to blood vessels and may therefore be simultaneously invaded by the tumour. In one report, a high EMVI score had been shown to predict the presence of N2 disease with low to moderate sensitivity (56%) and relatively high specificity (81%) [25]. The exact correlation between EMVI and the presence of nodal metastases, however, is not well established.

5.

Restaging after neoadjuvant treatment

Traditionally, restaging with MRI after neoadjuvant treatment had only a limited role, since the surgeon would proceed with the original surgical treatment plan as determined on the basis of the primary staging MRI, regardless of the response after chemoradiotherapy. Nowadays the role of restaging with imaging is emerging as surgeons recognise its value for planning the surgical approach. For example, if a tumour is shown to have downsized and retracted from initially invaded organs and/or the MRF, a standard total mesorectal excision (TME) instead of a more extended pelvic resection can be considered. Retraction from the anal canal may allow for sphincterpreserving surgery. Although still controversial, alternative treatments such as a local, transanal excision or deferral from surgery (a so called ‘wait-and-see policy) in the selected group of very good or complete responding patients have been reported by several groups with very promising results [26,27]. This paradigm shift in treatment puts the relevance of a restaging with imaging into a whole new perspective. Although the importance of a restaging MRI is acknowledged, there is no clear consensus on what should be the time interval between the completion of the neoadjuvant treatment and the response evaluation with imaging. It is believed that a longer interval (i.e. at least 6 weeks) provides better insight into the final treatment response.

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5.1.

41

Residual tumour versus fibrosis

Basically, a report of a restaging MRI should include an assessment of the same items as during primary staging (i.e. T-stage, MRF and N-stage). However, an important additional challenge in the restaging setting is the interpretation of post-treatment fibrosis. As a result of the chemoradiotherapy the tumour and nodes shrink and become fibrotic. On post-treatment T2W MRI this fibrosis is visualised as a hypointense bowel thickening at the previous site of the primary tumour or in the nodes. It is extremely difficult to differentiate between mere fibrosis and fibrotic tissues still containing (small) islets of residual tumour. Because radiologists will tend to over-stage rather than under-stage, relatively high over-staging rates (up to 50%) as compared with primary staging have been reported. Overall accuracies for determining the T-stage after chemoradiotherapy (the yT-stage) range between 43% and 60% [28,29]. More favourable results have been suggested for the selection of patients with a ‘good’ tumour response (i.e. tumour down-staging to yT0–2). It has been shown that post-CRT MRI can accurately predict tumours that are confined to the bowel wall (ypT0–2) with PPVs of 86–91% and NPVs of 70–75% [17]. However, for the specific selection of patients with a complete tumour response (yT0) results – in particular PPV – are much poorer, and up to 80% of patients with a complete response are over-staged as having residual tumour [15,30]. This suggests that, using standard MRI, it will be very difficult to select patients for a ‘wait-and-see’ policy.

5.2.

Tumour regression from the MRF

Similar to restaging of the tumour, the reassessment of the MRF is hampered mainly by difficulties in interpreting posttreatment fibrosis. In the case of residual fibrotic involvement of the mesorectal fascia, it is difficult to determine whether there is still actual tumour involvement and a substantial number of patients will be over-staged. However, there are some patterns that can help radiologists in confidently assessing tumour clearance from a previously involved MRF. If a fatpad of >2 mm reappears between the tumour and MRF, we can be confident that the MRF will be free of tumour. If there is only some residual (fibrotic) stranding into the MRF, the MRF will also be likely to be free of tumour [31]. NPVs in the range of 91–100% have been reported for reassessment of MRF involvement after CRT indicating that the patients with a free MRF can be reliably selected. PPVs, however, are much lower (ranging between 44 and 68%), reflecting the over-staging problems described above [18,28,31]. Park et al. suggested that the evaluation of tumour clearance from the MRF after CRT may be improved by the addition of diffusion-weighted imaging, although these results have not (yet) been confirmed by other studies [32].

5.3.

Lymph nodes and EMVI after chemoradiation

As a result of chemoradiation treatment the majority of the lymph nodes will decrease in size or even completely disappear. Hence, the median number and size of lymph nodes after CRT is significantly lower than at primary staging. The main aim of re-evaluating the nodal stage after CRT is to

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establish whether there are remaining metastatic nodes left inside but also outside the mesorectum, or if all initially suspicious nodes have become sterilised. In the latter case, a patient with a concomitantly good response of his primary tumour may be a candidate for organ-saving treatments (local excision or wait-and-see), yet at the time of writing this is still within the scope of clinical trials and not clinical routine. A careful comparison of nodes before and after chemoradiation is of crucial importance when interpreting nodes on post-CRT MRI. Also, a re-evaluation of any initially suspicious extramesorectal nodes should be performed in order to determine whether a lateral lymph-node dissection will be required. The diagnostic performance of post-chemoradiation MRI for restaging of the nodes is reported to be equal or slightly better than with primary staging MRI, with accuracies varying from 64% to 88% [28,33,34]. The criteria used for the restaging of nodes are similar to those used for primary nodal staging (size and, to a lesser extent, the nodal border and signal intensity), but it has been suggested by some authors that size criteria work better in the restaging setting. A possible explanation for this is that many irradiated nodes disappear, and of the remaining small nodes over 80% are sterilised [35]. Hence, nodes that remain large in size after CRT are more likely to be malignant. There is no evidence (yet) to support the benefit of the reevaluation of EMVI after CRT. In currently available literature EMVI has been assessed mainly in patients undergoing immediate surgery (without preoperative treatment). In the reports where patients undergoing neoadjuvant treatment were included, no subset analyses were performed to specifically investigate the value of assessing EMVI after preoperative CRT.

6.

Future perspectives

The time has passed when imaging was used to only provide information on tumour morphology. Functional imaging techniques give more comprehensive information on tumour morphology and underlying tissue characteristics. Some of these imaging biomarkers have already been implemented into clinical protocols, others are still under investigation. Multiparametric imaging in rectal cancer patients will significantly improve the radiologist’s performance, in particular for treatment response evaluation. Apart from that, technical developments in MR scanner hardware allow for innovative moving table techniques which generate whole-body MR images complementary to whole-body PET. The clinical introduction of hybrid PET–MR scanners combining both morphological and functional whole-body imaging within one single examination is the beginning of a new era.

6.1.

Diffusion-weighted MRI (DWI)

One of the most promising functional MR techniques for oncological imaging is diffusion-weighted MRI (DWI). Although originally used for the assessment of brain ischaemia, body applications of DWI are now also increasingly beginning to set the pace. DWI uses differences in the movement (‘diffusion’) of water protons between tissues with a

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different cellular density to differentiate between tumoural and non-tumoural tissues. Moreover, DWI can provide quantifiable data reflecting a tissue’s cellular structure, referred to as the apparent diffusion coefficient (ADC). Both the visual assessment of diffusion images, as well as the quantitative measurement of ADC, have shown great potential for rectal cancer imaging, in particular for the evaluation of the therapeutic response of rectal tumours after chemoradiotherapy. It has been shown by several authors that, compared with standard MRI, DWI offers significantly better diagnostic performance for the selection of patients with a good or complete response of their primary tumour after CRT, with reported AUCs up to 0.88 [30,36,37]. Although at present DWI is being investigated mainly in research settings and its true clinical potential has yet to be proven, DWI sequences are already frequently implemented into clinical protocols.

6.2.

Dynamic and lymph node contrast-enhanced MRI

Measurements of tumour microvascular perfusion are known to be valuable for cancer detection and treatment monitoring. Dynamic contrast-enhanced (DCE) or ‘perfusion’ MRI techniques could be a promising adjunct to morphological MRI in early response prediction. A pre-treatment measured Ktrans perfusion parameter has been shown in early studies to be valuable in distinguishing between patients with good or poor responses. Another potentially interesting topic in the field of lymph node imaging is the use of ‘lymph-node-specific’ MR contrast agents. Very promising results have been shown for the use of ultrasmall particles of iron oxide (USPIO), but this contrast has so far not been approved by the Food and Drug Administration for clinical use. Other MR contrasts such as gadofosveset-trisodium are currently being investigated. Although initial results seem very encouraging, these will need to be confirmed in large multicentre studies to warrant implementation into clinics.

7.

Conclusions and recommendations

Since the treatment for rectal cancer has emerged from a ‘one-size-fits-all’ strategy towards a personalised treatment plan based on a patient’s individual tumour risk profile, the role of the radiologist within the multidisciplinary team has changed. The radiologist now plays a full consulting role, and his imaging findings can influence treatment management. The current role of CTs (and PET–CTs) is mainly for the assessment of distant tumour spread. For local tumour staging MRI and EUS are the main players. EUS remains the best technique for the evaluation of low-risk, superficial tumours (T1–2) that may primarily be treated with (local) excision. For the evaluation of larger tumours, in particular for the assessment of large tumours that have a risk for invasion of the mesorectal fascia and neighbouring pelvic organs, MRI is the technique of first choice. Although lymph-node status is an important determinant for treatment, none of the currently available imaging modalities (CT, MRI or EUS) is sufficiently accurate to reliably assess the nodes. The role of imaging for restaging after neoadjuvant chemoradiotherapy is rapidly advancing. While previously the

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surgical treatment plan was established on the basis of the findings of primary staging, this plan may now be altered on the basis of the response of the tumour to CRT and the new findings at restaging imaging. The main difficulty after chemoradiotherapy is the differentiation on imaging between small residual disease and post-radiation fibrosis. Together with the dilemma of accurate nodal staging, these two challenges need to be addressed in the coming years. New hybrid and versatile MRI techniques, however, are on the horizon that may be able to offer a solution.

Conflict of interest statement None declared.

R E F E R E N C E S

[1] Ptok H, Marusch F, Meyer F, et al. Feasibility and accuracy of TRUS in the pre-treatment staging for rectal carcinoma in general practice. Eur J Surg Oncol 2006;32:420–5. [2] Carmody BJ, Otchy DP. Learning curve of transrectal ultrasound. Dis Colon Rectum 2000;43:193–7. [3] Wolberink SV, Beets-Tan RG, de Haas-Kock DF, et al. Multislice CT as a primary screening tool for the prediction of an involved mesorectal fascia and distant metastases in primary rectal cancer: a multicenter study. Dis Colon Rectum 2009;52:928–34. [4] Wiering B, Adang EM, van der Sijp JR, et al. Added value of positron emission tomography imaging in the surgical treatment of colorectal liver metastases. Nucl Med Commun 2010;31:938–44. [5] de Geus-Oei LF, Vriens D, van Laarhoven HW, van der Graaf WT, Oyen WJ. Monitoring and predicting response to therapy with 18F-FDG PET in colorectal cancer: a systematic review. J Nucl Med 2009;50(Suppl. 1):43S–54S. [6] Wallengren NO, Holtas S, Andren-Sandberg A, et al. Rectal carcinoma: double-contrast MR imaging for preoperative staging. Radiology 2000;215:108–14. [7] Slater A, Halligan S, Taylor SA, Marshall M. Distance between the rectal wall and mesorectal fascia measured by MRI: Effect of rectal distension and implications for preoperative prediction of a tumour-free circumferential resection margin. Clin Radiol 2006;61:65–70. [8] Vliegen RF, Beets GL, von Meyenfeldt MF, et al. Rectal cancer: MR imaging in local staging–is gadolinium-based contrast material helpful? Radiology 2005;234:179–88. [9] Lambregts DM, Beets GL, Maas M, et al. Accuracy of gadofosveset-enhanced MRI for nodal staging and restaging in rectal cancer. Ann Surg 2011;253:539–45. [10] Will O, Purkayastha S, Chan C, et al. Diagnostic precision of nanoparticle-enhanced MRI for lymph-node metastases: a meta-analysis. Lancet Oncol 2006;7:52–60. [11] Gollub MJ, Gultekin DH, Akin O, et al. Dynamic contrast enhanced-MRI for the detection of pathological complete response to neoadjuvant chemotherapy for locally advanced rectal cancer. Eur Radiol 2012;22:821–31. [12] Gollub MJ, Maas M, Weiser M, et al. Recognition of the anterior peritoneal reflection at rectal MRI. AJR Am J Roentgenol 2013;200:97–101. [13] Beets-Tan RG, Beets GL, Vliegen RF, et al. Accuracy of magnetic resonance imaging in prediction of tumour-free resection margin in rectal cancer surgery. Lancet 2001;357:497–504.

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[14] Bipat S, Glas AS, Slors FJ, et al. Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging – a meta-analysis. Radiology 2004;232:773–83. [15] Suppiah A, Hunter IA, Cowley J, et al. Magnetic resonance imaging accuracy in assessing tumour down-staging following chemoradiation in rectal cancer. Colorectal Dis 2009;11:249–53. [16] Kauer WK, Prantl L, Dittler HJ, Siewert JR. The value of endosonographic rectal carcinoma staging in routine diagnostics: a 10-year analysis. Surg Endosc 2004;18: 1075–8. [17] Dresen RC, Beets GL, Rutten HJ, et al. Locally advanced rectal cancer: MR imaging for restaging after neoadjuvant radiation therapy with concomitant chemotherapy. Part I. Are we able to predict tumor confined to the rectal wall? Radiology 2009;252:71–80. [18] MERCURY Study Group. Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer: prospective observational study. BMJ 2006;333:779. [19] Lahaye MJ, Engelen SM, Nelemans PJ, et al. Imaging for predicting the risk factors – the circumferential resection margin and nodal disease – of local recurrence in rectal cancer: a meta-analysis. Semin Ultrasound CT MR 2005;26:259–68. [20] Wang C, Zhou Z, Wang Z, et al. Patterns of neoplastic foci and lymph node micrometastasis within the mesorectum. Langenbecks Arch Surg 2005;390:312–8. [21] Kim JH, Beets GL, Kim JH, Kessels AGH, Beets-Tan RGH. Highresolution MR imaging for nodal staging in rectal cancer: are there any criteria in addition to the size? Eur J Radiol 2004;52:78–83. [22] Brown G, Richards CJ, Bourne MW, et al. Morphologic predictors of lymph node status in rectal cancer with use of high-spatial-resolution MR imaging with histopathologic comparison. Radiology 2003;227:371–7. [23] Talbot IC, Ritchie S, Leighton M, et al. Invasion of veins by carcinoma of rectum: method of detection, histological features and significance. Histopathology 1981;5:141–63. [24] Smith NJ, Shihab O, Arnaout A, Swift RI, Brown G. MRI for detection of extramural vascular invasion in rectal cancer. AJR Am J Roentgenol 2008;191:1517–22. [25] Koh DM, Smith NJ, Swift RI, Brown G. The relationship between MR demonstration of extramural venous invasion and nodal disease in rectal cancer. Clin Med Oncol 2008;2:267–73. [26] Maas M, Beets-Tan RG, Lambregts DM, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol 2011;29:4633–40. [27] Lezoche G, Baldarelli M, Guerrieri M, et al. A prospective randomized study with a 5-year minimum follow-up evaluation of transanal endoscopic microsurgery versus laparoscopic total mesorectal excision after neoadjuvant therapy. Surg Endosc 2008;22:352–8. [28] Kulkarni T, Gollins S, Maw A, et al. Magnetic resonance imaging in rectal cancer downstaged using neoadjuvant chemoradiation: accuracy of prediction of tumour stage and circumferential resection margin status. Colorectal Dis 2008;10:479–89. [29] Allen SD, Padhani AR, Dzik-Jurasz AS, Glynne-Jones R. Rectal carcinoma: MRI with histologic correlation before and after chemoradiation therapy. AJR Am J Roentgenol 2007;188:442–51. [30] Kim SH, Lee JM, Hong SH, et al. Locally advanced rectal cancer: added value of diffusion-weighted MR imaging in the evaluation of tumor response to neoadjuvant chemo- and radiation therapy. Radiology 2009;253:116–25.

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[31] Vliegen RF, Beets GL, Lammering G, et al. Mesorectal fascia invasion after neoadjuvant chemotherapy and radiation therapy for locally advanced rectal cancer: accuracy of MR imaging for prediction. Radiology 2008;246:454–62. [32] Park MJ, Kim SH, Lee SJ, Jang KM, Rhim H. Locally advanced rectal cancer: added value of diffusion-weighted MR imaging for predicting tumor clearance of the mesorectal fascia after neoadjuvant chemotherapy and radiation therapy. Radiology 2011;260:771–80. [33] Kuo LJ, Chern MC, Tsou MH, et al. Interpretation of magnetic resonance imaging for locally advanced rectal carcinoma after preoperative chemoradiation therapy. Dis Colon Rectum 2005;48:23–8. [34] Chen CC, Lee RC, Lin JK, Wang LW, Yang SH. How accurate is magnetic resonance imaging in restaging rectal cancer in

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patients receiving preoperative combined chemoradiotherapy? Dis Colon Rectum 2005;48:722–8. [35] Koh DM, Chau I, Tait D, et al. Evaluating mesorectal lymph nodes in rectal cancer before and after neoadjuvant chemoradiation using thin-section T2-weighted magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2008;71:456–61. [36] Lambregts DM, Vandecaveye V, Barbaro B, et al. Diffusionweighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study. Ann Surg Oncol 2011;18:2224–31. [37] Sun YS, Zhang XP, Tang L, et al. Locally advanced rectal carcinoma treated with preoperative chemotherapy and radiation therapy: preliminary analysis of diffusion-weighted MR imaging for early detection of tumor histopathologic downstaging. Radiology 2010;254:170–8.

Neoadjuvant therapy before surgical treatment Rob Glynne-Jones a b

a,* ,

Ian Chau

b,1

Mount Vernon Centre for Cancer Treatment, Northwood, United Kingdom Royal Marsden Hospital, Department of Medicine, Sutton, United Kingdom

A R T I C L E I N F O

Neoadjuvant treatment in terms of preoperative radiotherapy reduces local recurrence in rectal cancer, but this improvement has little if any impact on overall survival. Currently performed optimal quality-controlled total mesorectal excision (TME) surgery for patients in the trial setting can be associated with very low local recurrence rates of less than 10% whether the patients receive radiotherapy or not. Hence metastatic disease is now the predominant issue. The concept of neoadjuvant chemotherapy (NACT) is a potentially attractive additional or alternative strategy to radiotherapy to deal with metastases. However, randomised phase III trials, evaluating the addition of oxaliplatin at low doses plus preoperative fluoropyrimidine-based chemoradiotherapy (CRT), have in the main failed to show a significant improvement on early pathological response, with the exception of the German CAO/ARO/AIO-04 study. The integration of biologically targeted agents into preoperative CRT has also not fulfilled expectations. The addition of cetuximab appears to achieve relatively low rates of pathological complete responses, and the addition of bevacizumab has raised concerns for excess surgical morbidity. As an alternative to concurrent chemoradiation (which delivers only 5–6 weeks of chemotherapy), potential options include an induction component of 6–12 weeks of NACT prior to radiotherapy or chemoradiation, or the addition of chemotherapy after short-course preoperative radiotherapy (SCPRT) or chemoradiation (defined as consolidation chemotherapy) which utilises the ‘‘dead space’’ of the interval between the end of chemoradiation and surgery, or delivering chemotherapy alone without any radiotherapy. Copyright  2013 ECCO - the European CanCer Organisation. All rights reserved.

1. Rectal cancer: neoadjuvant therapy before surgical treatment Rectal cancer is a very heterogeneous disease with different prognostic implications and varying outcomes. Historically, a high local recurrence rate has dominated decision-making. The need for radiation treatment has become deeply ingrained in surgical and radiation oncology culture, prompted by an imperative to avoid local pelvic recurrence at all costs. Local recurrence can be associated with intractable pelvic pain, tenesmus, mucinous discharge and intestinal obstruction, and few patients can be saved [1]. However, recent data suggest that metastases are now the predominant problem [2]. In a pooled analysis of 2795 patients recruited in five Euro-

pean randomised controlled trials, the 5-year distant metastasis rate was 30.8% [3]. Initially, because of the lack of reliable preoperative imaging, attempts to improve outcomes centred on postoperative chemoradiation according to pathological staging. With the emergence of more sophisticated imaging, this strategy has been extrapolated to the neoadjuvant arena, and validated by further phase III trials. Management has therefore moved from a solely surgically treated disease to the current widespread use of neoadjuvant radiation or combined chemotherapy and radiation therapy. Over the past 3 decades the neoadjuvant management philosophy has also evolved independently in different regions of the world. The individual phase III studies performed

* Corresponding author Tel.: +44 (0) 1923 844767; fax: +44 (0) 1923 844 138. E-mail addresses: [email protected] (R. Glynne-Jones), [email protected] (I. Chau). 1 Tel.: +44 208 661 3582; fax: +44 208 661 3890. 1359-6349/$ - see front matter Copyright  2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.032

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in each country have driven the precise patterns of care. In the United Kingdom refinements in surgical technique – i.e. total mesorectal excision (TME) and extralevator abdominoperineal excision (ELAPE) [4,5] coupled with improvements in the quality of such surgery [6] – and the use of MRI and universal multidisciplinary team (MDT) discussion, have ensured that isolated local recurrence is now a rare event in 2012, if the surgeon can perform a good quality TME, even without radiotherapy [6]. However, even with expertly performed TME, the rate of distant recurrence has been documented as 18% in stage II patients and 37% in stage III patients in one important retrospective series [7]. Recently there has been enthusiasm for integrating more active systemic chemotherapy to increase down-staging and response and to lessen the risk of metastatic disease. In stage III colon cancer adjuvant chemotherapy based on 5-fluorouracil (5FU) reduced the risk of recurrence and prolonged survival, and hence has been firmly established and recommended as adjuvant treatment in patients following a curative resection [8]. More recent studies have confirmed that the addition of oxaliplatin to 5FU-based chemotherapy improves disease-free survival (DFS) [9,10] and overall survival (OS) [10] in patients with stage III colon cancer (although rectal cancers within 12 cm of the anal verge were excluded from these studies). FOLFOX is now considered an international standard as adjuvant chemotherapy for colon cancer in stage III disease, although there is still controversy regarding its use in high-risk stage II colon cancer. Yet the role of adjuvant chemotherapy in rectal cancer is not as clear-cut as in stage II and stage III colon cancer, and the validity of this standard has been questioned in a recent meta-analysis [11]. In Northern Europe short-course preoperative radiation therapy (SCPRT) (25 Gy in five fractions) followed by immediate surgery was evaluated as an adjunct to surgery [12,13]. Early trials showed an improvement in survival [12], and there have been subsequent consistent reports of lower local recurrence rates in randomised trials [14,15]. Yet integration into routine practice in other parts of the world has always been slightly tempered by early reports of severe acute and longterm toxicity [12,13,16]. When directly compared with standard chemoradiotherapy (CRT), SCPRT shows similar efficacy [17,18]. The recent TROG 01.04 trial in clinical stage T3 rectal cancer compared SCPRT with long-course preoperative CRT [18]. The trial confirmed similar outcomes for SCPRT and CRT for distant recurrence, overall survival and late effects. After a minimum follow-up period of 3 years cumulative incidences of local recurrence at 5 years were 7.5% for SCPRT and 5.7% for CRT respectively (P = 0.51). For distal tumours, six of 48 SCPRT patients and one of 31 CRT patients had a local recurrence (P = 0.21). In the landmark German l CAO/ARO/AIO – 94 Trial [19] a total of 823 patients were randomised between preoperative CRT and postoperative CRT (patients received postoperative adjuvant chemotherapy in both arms of this trial). Acute and late toxicities were significantly reduced with the preoperative approach, although it should be recognised that a higher radiation dose was mandated for the postoperative regimen. Loco-regional failure was only 6% in the preopera-

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tive arm versus 13% in the postoperative arm. There was, however, no difference observed in the distant metastases rate, DFS or OS. This advantage is also supported to some extent by the National Surgical Adjuvant Breast and Bowel Project (NSABP R-03) trial results [20] which showed a statistically significant improvement in 5-year DFS (65% versus 53%, P = 0.011) for preoperative therapy (although it included an additional 6 weeks of neoadjuvant chemotherapy). Both trials have therefore served to validate the benefit of neoadjuvant 5FU-based chemoradiotherapy for locally advanced rectal cancer compared with postoperative therapy. Hence, randomised controlled trials have unequivocally demonstrated that preoperative radiotherapy or chemoradiation [12,13,20–23] is more effective than postoperative chemoradiation therapy in terms of reducing local recurrence, and with less acute and late toxicity than postoperative therapy. Yet the risk of dying from rectal cancer is linked mainly to the development of distant metastases, and to experience a late local recurrence as described by Sauer et al. [23] the patient needs to survive 5 years. As an alternative setting to concurrent chemoradiation (which only delivers 5–6 weeks of chemotherapy), potential options are an induction component of 6–12 weeks of neoadjuvant chemotherapy (NACT) prior to radiotherapy or chemoradiation [20,24–27], adding chemotherapy after SCPRT or chemoradiation (defined as consolidation chemotherapy) which utilises the ‘‘dead space’’ of the interval between the end of chemoradiation and surgery [28–30], or delivering chemotherapy alone without any radiotherapy [31,32]. In Valentini’s recent pooled analysis of seven chemoradiation trials, the most effective predictive model for developing local recurrence was based on ypT stage, cT stage, age, ypN stage and concomitant delivery of adjuvant chemotherapy. Hence the only preoperative data available were age and cT status. The best model for predicting distant metastases used ypN stage, ypT stage, surgical procedure and delivery of adjuvant chemotherapy (in order of relevance). Hence these nomograms are unhelpful in the preoperative setting [3]. More recently, outcomes have been shown to vary according to predicted (i.e. clinical) T stage of disease (Table 1), and other prognostic factors (mainly extramural vascular invasion and tumour extent in relationship to the circumferential resection margin), which can be determined by preoperative magnetic resonance imaging (MRI). Hence a more individualised approach to treatment selection is now feasible according to the relative risk of local recurrence versus metastatic disease. However, the consistently accurate parallels between clinical imaging and pathological staging obtained in the MERCURY study have not been easily reproduced. Both the technical aspects and the immediate demands of the presence of a specialist radiologist for optimal MRI imaging, and the interpretation of the scans, mean there is a significant degree of individual variation between and within centres. All of these factors have contributed to a variable acceptance of the technique worldwide. In this article for the ESMO educational symposium we discuss the various available options for neoadjuvant therapy, their rationale and the results obtained. We consider the different approaches of long-course CRT and SCPRT: the intensi-

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47

1 1 ( 2 0 1 3 ) 4 5 –5 9

Table 1 – Japanese-style surgery with laparoscopic pelvic lymph-node dissection (LPLND). Risk of local recurrence and distant metastases. Cut-off for depth of mesorectal involvement 64 mm.

64 mm >4 mm

Stage IIA

Stage IIIB

All Stage III

Distant metastases

12/295 (4.1%) 21/295 (7.1%)

14/204 (6.9%) 36/204 (17.6%)

21/245 (8.6%) 47/245 (19.2%)

Distant metastases

13/295 (7.7%) 28/168 (16.7%)

23/218 (10.6%) 58/218 (26.6%)

34/267 (12.7%) 75/267 (28.1%)

Local recurrence Local recurrence

fication of preoperative radiation and chemoradiation with dose-escalation of external-beam radiotherapy (EBRT), using brachytherapy, intraoperative radiotherapy (IORT), hyperfractionation and various available techniques such as intensitymodulated radiotherapy (IMRT). We make recommendations as to which clinical or imaging features require preoperative CRT or SCPRT to be delivered, and where it could possibly be avoided. The strategies of neoadjuvant, concurrent, consolidation (i.e. immediately following chemoradiation and prior to surgery) chemotherapy with cytotoxic agents are explored. We speculate on the initial attempts to integrate biological agents as future potential strategies of treatment with and separate from radiation. The current era of precision imaging offers many options for conformal external-beam radiotherapy, such as IMRT, volumetric arc therapy (VMAT), brachytherapy and a plethora of systemically active cytotoxic and biological agents. Practice has also been driven more recently by meticulous refinements in surgical technique, in which all the surrounding mesorectal fat are removed in a neat anatomical package (total mesorectal excision and extralevator abdominoperineal excision), the availability and quality of preoperative MRI to determine potential risks, an increasing value placed on histopathology and assessments/metrics of the quality of surgery. TME is associated with much lower rates of local recurrence and improved survival [4], but all these advances have contained and driven down the local recurrence rate. In 2005, investigators from Hong Kong challenged the accepted wisdom and questioned whether low-risk stage II patients benefit from neoadjuvant therapy [33]. With a median follow up of 43 months, they reported a 6% local recurrence rate at 5 years for patients undergoing anterior resection (with a median level of tumour at 8 cm from the anal verge). Recent population-based data [34] and retrospective series exploiting these advances further undermine the approach of a blanket use of radiotherapy/chemoradiation by exploring the omission of radiotherapy when MRI suggests the tumour is easily resectable and the circumferential resection margin (CRM) is not threatened [35–38]. Others have also recently questioned the routine use of chemoradiation for rectal cancer [39,40]. The current high clinical and pathological response rates [41] observed from chemotherapy in small clinical trials also offer an alternative option to chemoradiation. So the rationale for selecting patients suitable and appropriate for neoadjuvant preoperative radiotherapy/chemoradiotherapy needs reconsidering.

For patients with resectable rectal cancer prior to the current TME era, trials of CRT or SCPRT demonstrate a reduction in loco-regional failure (LRF), but without extending DFS or OS. More recent randomised trials in locally advanced rectal cancer (LARC) suggest that the high historical local recurrence rate of the 1990s has been reduced to 7 weeks between neoadjuvant therapy and surgery improves pathologic complete response and disease-free survival in patients with locally advanced rectal cancer. Ann Surg Oncol 2008;15:2661–7. Sloothaak DA, Geijsen DE, van Leersum NJ, et al. On behalf of the Dutch Surgical Colorectal Audit. Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg 2013 March 27. http:// dx.doi.org/10.1002/bjs.911 [Epub ahead of print]. Stein DE, Mahmoud NN, Anne´ PR, et al. Longer time interval between completion of neoadjuvant chemoradiation and surgical resection does not improve downstaging of rectal carcinoma. Dis Colon Rectum 2003;46:448–53. Kerr SF, Klonizakis M, Glynne-Jones R. Suppression of the postoperative neutrophil leucocytosis following neoadjuvant chemoradiotherapy for rectal cancer and implications for surgical morbidity. Colorectal Dis 2010;12:549–54. Uehara K, Ishiguro S, Sakamoto E, et al. Phase II trial of neoadjuvant chemotherapy with XELOX plus bevacizumab for locally advanced rectal cancer. Jpn J Clin Oncol 2011;41(8):1041–4.

The modern anatomical surgical approach to localised rectal cancer R.G. Orsini a, T. Wiggers b, M.C. DeRuiter c, P. Quirke d, R.G. Beets-Tan e, C.J. van de Velde f, H.J.T. Rutten a,g,* a

Catharina Hospital, Eindhoven, The Netherlands University Medical Centre Groningen, Groningen, The Netherlands c Leiden University Medical Centre, Leiden, The Netherlands d Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK e GROW School for Oncology & Developmental Biology, Department of Radiology, Maastricht University Medical Centre, Maastricht, The Netherlands f Leiden University Medical Centre, Leiden, The Netherlands g GROW School for Oncology & Developmental Biology, Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands b

1.

Introduction

On a worldwide scale, colorectal cancer is one of the leading causes of cancer deaths, affecting millions of people every year. One third of colorectal cancer concerns the rectum. In more than two thirds of the cases rectal cancer is still localised to the pelvis without detectable metastases. In these cases surgical resection is the cornerstone for a curative approach. Since the introduction of the combined abdominoperineal resection by Miles and Que´nu around the beginning of the 20th century [1], rectal cancer became a curable disease. However, for many decades the results of surgery have been disappointing, as it was often spoiled by a local recurrence rate of up to 40% or even higher. Uncontrolled progressive local recurrences, hardly palliated by irradiation or chemotherapy, have brought a miserable death to tens of millions of patients. This situation lasted till the end of the last century when the anatomical basis of rectal cancer surgery was revived by Heald and Quirke [2,3]. Quirke demonstrated that the radial margin between the tumour border and the surgical resection margin was a strong prognosticator for local recurrence. He pointed out that both tumour progression and surgical quality were important for a safe margin. Poor surgery with incomplete mesorectum or tears into the mesorectal fat or muscular tube of the rectum could reduce this margin and consequently lead to local recurrences. Heald introduced the principle of total mesorectal excision (TME). In doing so he defined the optimal quality of surgery.

Worldwide surgeons have accepted as standard of care that optimally the rectum has to be removed within its enveloping mesorectal fascia. TME emphasises the importance of an anatomical resection in the planes between the mesorectal fascia and the surrounding pelvic fascias. However, the principle of resection of the rectum within its mesorectal fascia seems to fail when analysing low rectal cancer. From the early randomised controlled trials it was learned that patients requiring an abdomino-perineal excision (APE) still had high positive circumferential resection margins [4–7]. The lower rectum and anorectum are not surrounded by a protecting layer of mesorectal fat. Instead, already in an early stage, progressing tumours reach and possibly infiltrate the pelvic floor muscles, which are continuous with the external sphincter more distally. Compared with patients undergoing low anterior resection (LAR) APE patients have tumours located lower and more advanced, therefore new principles of surgery had to be developed [8]. Results of lower rectal cancer surgery improved when the principle of the extra levator approach was introduced [9– 12]. This involves removal of the lower rectum during an abdomino-perineal excision en bloc with the external sphincter and levator ani muscles. In the lower rectum the role of complete removal of the mesorectal fascia is replaced by removal of the levator ani muscles. Again, the quality of the surgery can be judged by the completeness of this resection. Modern rectal cancer surgery can be tailored to the specific topographical relationships of the tumour. In proximal tumours the mesorectal fascia acts as the guiding structure. Transection of the specimen can be performed 4–5 cm distally

* Corresponding author at: Department of Surgery, Catharina Hospital, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands. Tel.: +31 40 2397155. E-mail address: [email protected] (H.J.T. Rutten). 1359-6349/$ - see front matter Copyright  2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.033

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from the lower tumour border or at the pelvic floor when the mesorectum terminates higher. More distal tumours can be removed by either intersphincteric resection – if the tumour is confined within the smooth muscle tube of the muscularis propria, sometimes even allowing for a colo-anal anastomosis – or extralevator resection if the pelvic floor is threatened or already involved by tumour progression. The third option for an abdomino-perineal excision is to take an even wider approach, taking out the ischiorectal fat en bloc with the levator muscles, if the tumour has perforated or fistulated through the pelvic floor muscles into this fatty area. However, this will be the case only in extremely rare circumstances. Modern rectal cancer surgery is part of a multidisciplinary approach. Preoperative imaging with magnetic resonance imaging (MRI) is able to delineate the tumour very accurately and helps to select those patients requiring downsizing and down-staging, optimising the chances of a good tumour resection [13–15]. The pathologist plays an important role in the feedback to the surgeon, which is necessary to improve surgical outcome [16]. The first step in integration of optimal imaging, treatment modalities and pathology is taken is several countries. The next step will be to optimise treatment for the individual patient, who is interested not only in the oncological outcome but also in functional results and subsequent quality of life. Avoiding and decreasing morbidity, especially in the elderly, will require the development of new innovative strategies.

2. Contribution of pathology to the anatomical approach It may seem odd to start a discussion on modern surgical approaches to localised rectal cancer with the findings of the pathologist. However, it was a pathologist who demonstrated the importance of the distance of the radial tumour border to the mesorectal fascia, which is called the circumferential resection margin (CRM) in TME surgery [3]. In 2002 Nagtegaal analysed the data of the Dutch TME study, and she confirmed that in 44% of the patients the involved circumferential resection margin was the result of poor-quality surgery. It was also shown that, after incomplete mesorectal excision, the overall recurrence rate was almost doubled, which could be attributed mainly to the excess of local recurrences [16]. Nagtegaal and Quirke performed a metaanalysis on the importance of the CRM in more than 17,500 patients and concluded that CRM involvement predicts not only local recurrence but also distant metastasis and subsequent overall survival. Failure to achieve a negative CRM after neoadjuvant treatment leads to a poorer prognosis compared with no neoadjuvant treatment. Possibly the explanation for this is the selection of patients with tumours more resistant to therapy. This finding could be an argument for restaging after neoadjuvant therapy, and to consider more prolonged neoadjuvant treatment, or to refer to a specialised centre for more extended resection or additional boosting of the area at risk [17]. Thus, the actual feedback of the pathologist to the surgeon should contain information on the CRM and quality of surgery [18]. Another important issue, which will be discussed la-

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ter in this paper, is the evaluation of the effectiveness of the chosen neoadjuvant treatment. Preferably, macroscopic images of the resected specimens, as well as the microscopic images, should be available for internal audit and continued education and improvement of all member decisions during the multidisciplinary tumour board meetings. Quirke proposed a 3-point grading system for the evaluation of the macroscopic specimen for both low anterior and abdomino-perineal resections. Good surgery would be qualified by an intact mesorectal fascia with only minor irregularities, or in the case of APE, a specimen with levator ani and external sphincters without any defects deeper than 5 mm and the levator ani attached to the mesorectal fascia [19,20] (see Figs. 1–3). After moderate-quality surgery the bulk of the mesorectum is removed but shows an irregular surface, however still without exposing the muscularis propria or perforations. In the case of an APE, a specimen which shows waist formation, indicative for a less complete levator ani covering at the anorectal junction, but with intact sphincters, signifies a moderate quality of surgery. Poor surgery would be characterised by severe irregularities on the surface of the specimen, exposing the muscularis propria or internal sphincter or even showing perforations to the lumen. Very essential for the grading of the APE specimen is the question of whether the levator ani muscle is still attached to the mesorectum. Thus, waist formation is avoided and the result is a more cylindrical resection. In order to achieve optimal feedback, pathology reports should be standardised, not only regarding the reporting of the TNM status, but also on the quality of surgery [19].

3. The importance of MRI for the surgical treatment of rectal cancer Magnetic resonance imaging (MRI) is a reliable diagnostic tool for clinical staging of rectal cancer, but other imaging methods for the pelvis are also being used for this purpose. Computed tomography (CT) is able to identify enlarged lymph nodes, although it is not accurate for assessing the morphology of these nodes. Furthermore, the contrast resolution of CT is insufficient to reliably assess involvement of the surgical resection plane in mid and lower rectal cancer. CT, however, is indicated for distant staging of metastatic disease and, if there is no easy access to an MRI, for assessment of resectability of high rectal tumours [21–23]. Endorectal ultrasound (EUS) cannot visualise the mesorectal fascia, but is the modality of choice to differentiate between T1 and T2 lesions for the selection of local therapies. EUS has a high sensitivity to stage depth of submucosal involvement [24]. However, MRI is the king of kings of all imaging modalities in its tissue contrast resolution and provides the necessary detailed anatomical information on pelvic fascias and dissection planes between pelvic soft tissues, which sets the scene for the planning of the resection. Without the anatomical topographical information of an MRI, the surgeon has to rely on ad hoc decisions when unexpected problems occur during the actual surgical procedure

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1 1 (2 0 13 ) 6 0–71

Fig. 1 – Rectal extralevator abdomino-perineal excision specimen. The solid yellow lines indicate the intact mesorectum. The red lines demonstrate the extralevator muscles attached to the specimen covering widely the anorectal junction (white arrow) where the mesorectum ends and the internal sphincter starts (dotted yellow line). Even advanced T3 or T4 tumours at the anorectal junction and below can be safely removed when covered by the extralevator muscle layer. Typically a cylindrically shaped specimen. Mesorectum intact. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2 – ‘Standard’ abdomino-perineal excision specimen, demonstrating waist formation at the anorectal junction or just above (white arrow). Only marginal coverage by the external sphincters of the distal mesorectum. Will suffice for less advanced tumours of the anorectum or anorectal junction. Specimen characterised by ‘waist’ formation. Mesorectum intact.

and in a worst-case scenario these problems may even go unnoticed, or have become irreversible. With the anatomical information from MRI critical sites of resection can be

anticipated and addressed before surgery: i.e. use of neoadjuvant treatment or referral to a centre specialised in extended extra anatomical pelvic resection if TME surgery is not justified.

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1 1 ( 2 0 1 3 ) 6 0 –7 1

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Fig. 3 – Poor specimen after abdomino-perineal excision. Deep indentations and even perforation in mesorectum. Very little coverage of the external sphincter and showing tears in the external sphincter.

The Mercury study group reported the reliability of MRI on predicting extramural depth of tumour invasion. Very good correlation of extramural spread on MRI and histopathology was found: the 95% confidence interval being 1 mm and 2 and 5 mm carried a similar risk for local recurrence of around 7%, in contrast to the 20% risk of patients with an anticipated margin of 7 cm: T3 See Table 2

[22]

5

Subclassification of T1/2 according to largest tumour diameter Reclassification of synchronous additional tumour nodules (ATNs) New borders for mediastinal lymph-node stations Reclassification of malignant pleural/ pericardial effusion Subclassification of M1

6 7

Use of TNM in SCLC and carcinoid tumours Appropriate (sub)stage regrouping (Fig. 1)

8

Elimination of Mx descriptor

9

Optional descriptor for pleural (Pl) invasion

1 2 3 4

10

[22] [28]

M1a

[26]

Limited to thorax: M1a; extrathoracic spread: M1b

[26]

T2bN0 becomes stage IIA instead of IB; T2aN1 becomes IIA instead of IIB; T4N0/1 becomes IIIA instead of IIIB The clinical assessment of metastasis can be based on physical examination alone (cM0/1); pM0 should be restricted to autopsy cases. Else, the pathologist should refer to cM Tumour growth under internal elastic layer: Pl0 – through elastic layer but not abutting pleural surface: Pl1, T upgrading to at least T2a – abutting pleural surface: Pl2; T upgrading to at least T2a – in parietal pleura: Pl3; T upgrading to at least T3 – cannot be assessed: PlX Pn0: no perineural invasion, Pn1: perineural invasion, PnX: perineural invasion cannot be assessed

Optional descriptor for perineural (Pn) invasion

rately, or if a single TNM category is required, the highest T category and stage of disease should be assigned and the multiplicity of the lesions categorised as (m), or the number of tumours should be indicated in parentheses, for example: T2(m) or T2(5). If the lesions are concluded to be metastases, then the appropriate T or M category will be dependent on the site of the nodules (Table 2). If in the same lobe as the primary they are now classified as T3 and, when associated with node negativity, are stage IIB. When associated with N1 or N2 disease they are now classified as stage IIIA, not IIIB. Tumours associated with additional nodules in other ipsilateral lobe(s) have been reclassified as T4 rather than M1. When associated with N0 or N1, these patient cases should be designated as stage IIIA, and with N2 or N3 as stage IIIB. Tumours associated with additional nodules in the contralateral lung remain M1 but have been reclassified as M1a. The T4 descriptor remained unchanged, but when associated with N0 or N1 disease, it was down-staged to stage IIIA, not IIIB. Tumours associated with malignant pleural/pericardial effusion or pleural/pericardial nodules have been reclas-

[35–37] [23]

[19]

[38]

[19]

sified as M1a rather than T4 [26]. These data reflect the algorithm previously developed to treat patients with socalled wet IIIB disease with systemic therapy. Tumours associated with distant metastases have been reclassified as M1b. Analysis of the IASLC database allowed validation of the existing N categories, which were adopted without change [27]. Both existing lymph-node maps were unified in the IASLC nodal map [28], and the precise anatomical definitions of each nodal station are now recognised by the UICC and AJCC as the recommended means of describing regional lymphnode involvement for lung cancer. An important modification to both previous maps is the observation that the anatomical and oncological midlines in the superior mediastinum no longer coincide. The oncological midline deviates to the left lateral border of the trachea at the thoracic inlet and returns to the midline at the carina. Thus, all nodes in the superior mediastinum that lie anterior to the trachea are grouped with right upper paratracheal station 2 and right lower paratracheal station 4. Involvement of these nodes by a right-sided tumour will now be classified as N2-disease, whereas for a

Table 2 – The fate over time of multiple synchronous primary tumours.

Same lobe as primary tumour Same lung, other lobe Other lung

UICC 5, recommendation [8]

UICC 6 [11–13]

UICC 7 [17–20,22]

Tn +1

T4; at least stage IIIB

T4: at least stage IIIB M1: stage IV

M1: stage IV M1: stage IV

T3N0: stage IIB; 3N1/2: stage IIIA; T3N3: stage IIIB T4N0/1: stage IIIA; T4N2/3:stage IIIB M1a: stage IV

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left-sided tumour, this will become N3-disease. This is in keeping with the observations of some Japanese colleagues [29]. In addition, the concept of nodal zones has been introduced, amalgamating adjacent nodal stations into larger anatomic units. An exploratory analysis of the IASLC database studied survival after complete resection in relation to the extent of node involvement using the zonal concept. Three groups were identified, with significant differences in survival. Those with single-zone N1 disease had the best survival, at 48% over 5 years. Patients with multizone N2 disease had the worst survival, at 20% over 5 years. The third group, with intermediate survival, consisted of patients with multizone N1 (35% 5-year survival) and those with singlezone N2-disease (34% 5-year survival). This refinement is presently under investigation, in order to make the nodal map of greater use to oncologists and radiologists, who are frequently tasked with classifying more bulky nodal disease that might transgress the boundaries of individual nodal stations. As many as 40% of the reports on lung cancer resection specimens contains no information on mediastinal node involvement [30]. It is known that the greater the number of lymph nodes removed at thoracotomy, the higher the survival rate [31,32], even if all nodes are shown to be negative, presumably by increasing the certainty of the N0 classification [33]. The development of an internationally agreed nodal classification has allowed the reintroduction of minimum requirements for nodal assessment at surgery and subsequent pathological evaluation. In the latest edition of TNM, there is now an expanded definition of complete resection (R0), which recommends that at least six lymph nodes/nodal stations be removed/sampled and confirmed on histology to be free of disease to confer pN0 status [34]. Three of these nodes/stations

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should be mediastinal, including the subcarinal nodes (station 7) and three from N1 nodes/stations. It is hoped that the setting of this basic standard will improve nodal assessment and thereby the outcomes of pulmonary resection for lung cancer. The above mentioned modifications in T and N have led to a migration of cases in between pre-existing (sub)stages (Fig. 1): T2bN0 becomes stage IIA instead of IB; T2a N1 becomes IIA instead of IIB; T4N0/1 becomes IIIA instead of IIIB. Small-cell lung cancer has always been excluded from the TNM classification. However, the seventh edition is the first to show that TNM has greater utility than the limited versus extensive stage split commonly used in clinically staged patients as well as those treated surgically, especially as a stratification factor in clinical trials of earlier-stage disease [35,36]. Although the TNM classification was already used in both the typical and atypical variants of carcinoid tumours, the seventh edition is the first to validate this practice [37]. There has never been an internationally agreed definition of visceral pleural invasion (VPI). This created difficulties for the IASLC staging project when attempting to define the interrelationship between VPI and other prognostic factors such as tumour size. An internationally agreed definition was therefore developed, in which VPI is defined as ‘invasion beyond the elastic layer including invasion to the visceral pleural surface’ [38]. In addition, a comment was added recommending the use of elastic stains when this feature is not clear on routine histology. With these refinements, VPI was carried forward into the seventh edition without change, and the IASLC proposed an optional more detailed classification of pleural invasion, adapting the P category developed by the Japan Lung Cancer Society to create a PL classification [39,40]. The impact of visceral pleural invasion on survival according

Fig. 1 – Stage groups according to tumour–node–metastasis (TNM) descriptor and subgroups. Reprinted with permission from Detterbeck et al [20]. >7: diameter >7 cm; Inv: invasion; Satell: satellite nodule in same lobe; Ipsi Nod: nodule in ipsilateral lung; Contr Nod: nodule in contralateral lung; Pl dissem: pleural or pericardial dissemination.

154

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to size was reported according to the seventh UICC classification and confirmed its proposed Pl descriptor [41]. Other changes, generic to the seventh edition of UICC, are the elimination of Mx and the introduction of a descriptor of perineural invasion Pn.

1 1 ( 20 1 3) 1 5 0–15 8

edition, 211 (29%) stage IB patients migrated to stage II and 161 (48%) patients migrated from stage IIB to IIA. Stage migrations could change the treatment for up to 326 (17.3%) of the patients in this series [43].

1.4. 1.3.

Strengths

Implications of the 7th edition

Several authors have addressed the magnitude of the impact of the modifications on stage grouping. Van Meerbeeck et al estimated that in the IASLC data set of 15,952 resected patients, the change of p-TNM staging classification from UICC 6 to 7 results in the net migration of 23% of resected cases: stage pIB (–1326), stage pIIA (+2017), stage pIIB (±730), stage pIIIA (+701), stage pIIIB (–745) and stage pIV (+83) (Fig. 2) [42]. The magnitude of up- and down-migration is similar. Substage migration resulted in an increase in 5-year survival of 4% in p-IB and a decrease of 10% in p-IIIB. This stage migration should be accounted for when comparing outcome across surgical series using different TNM classifications. In a Norwegian cancer registry series from 2001–2005, the concordance index was 0.68 for both editions, indicating no overall difference in their predictive accuracy [43]. In the seventh

Lung cancer stage definitions have never been subjected to such an intense validation process [44]. Internal validity was addressed by visually assessing the consistency of Kaplan– Meier curves across database types and geographic regions. External validity was addressed by assessing the similarity of curves generated using the population-based Surveillance Epidemiology and End Results (SEER) cancer registry data to those generated using the project database. Cox proportional hazards regression was used to calculate hazard ratios between the proposed stage groupings with adjustment for cell type, sex, age and region. Validation checks were robust, demonstrating that the suggested staging changes were internally and externally stable. Several series coming from cancer registries and surgical series have confirmed some or all of the proposed modifications, adding supplementary external validation to the classification [45,46].

Fig. 2 – (A) Stage migration from sixth to seventh tumour–node–metastasis (TNM) classification in resected cases. (B) Impact of stage migration on overall survival. Reproduced with permission from Van Meerbeeck et al [42].

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1.5.

Weaknesses

Taken together, the proposed changes are limited in number and most are either intuitive or reflect modifications that were already suggested in the analysis of cancer registries or surgical series. As some of these series were included in the IASLC database, these modifications are self-fulfilling. With respect to the proposed boundaries for lymph-node stations, they represent a clear improvement for surgeons, but are not unambiguous for radiologists and echo-endoscopists. A recent ultrasonographic lymph-node map based on the anatomical boundaries of the seventh UICC classification might well resolve this issue [47]. The abovementioned reshaping of mediastinal lymph-node borders will result in an increase in so-called ‘minimal N2’, limited to a single station. The magnitude of this phenomenon has not yet been reported. Furthermore, stage IIIA, which used to be heterogeneous in the sixth classification, becomes a cocktail of six different T/N combinations. Even a database of 67,000+ patients was not able to validate all the descriptors that had accrued within previous editions of TNM. One should remember, however, that many of these data were not originally defined for the purpose of evaluating the staging system, but with some other scientific questions in mind. Their prognostic role was not always confirmed by multivariate analysis. Among the T descriptors that need further study are: (1) The best way to assess tumour size clinically: measuring a single diameter, measuring the greatest diameter or measuring two or three dimensions. Computed tomography (CT) screening has accelerated the development of volumetric software, adding to the debate as to how best to determine tumour size, and whether or not volume is preferable over size [48]. (2) The non-size-based descriptors of T2/3 as hilar atelectasis, obstructive pneumonitis and the cytology-negative paramalignant pleural effusion (not considered as a T-modifying condition) [49]. It is hoped that the use of [18]fluorodeoxyglucose–positron emission tomography (FDG-PET) scanning may help unravel the inflammatory and neoplastic elements. (3) The split of which invasion to adjacent structures is assigned to T3 or to T4 could not be answered because there were too few patient cases in which the precise descriptor justifying the T3 or T4 category was recorded, and even fewer in which all of the other descriptors were known to be absent. (4) The extent of dissemination was only partly addressed by the introduction of M1a. The recently increasing interest in the outcome of oligometastatic disease could not be translated into a separate descriptor for this entity. Other details and areas in which ambiguities and difficulties exist have been reviewed [50].

1.6.

Threats

Although the data are definitely more recent than in previous TNM editions, they still are from the past century and do not

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reflect present-day staging and treatment paradigms, wherein FDG-PET and endoscopic ultrasound are now standard staging techniques for the M and N descriptors. It has been shown in several series that the introduction of both techniques has significantly improved the accuracy of clinical staging and upstaged the stage distribution at diagnosis, hence changing treatment algorithms and improved stagespecific outcomes [51]. This process of improved stage-specific survival has been described previously at the occasion of a previous revision of the lung cancer TNM [52]. This socalled Will Rogers phenomenon has been observed in stage III patients, where the outcome was significantly ‘improved’ by the occurrence of PET staging [53–55]. Whereas pathological staging has a prognostic significance, clinical staging is meant to help the clinician in treatment allocation. The interaction between better staging techniques and improved treatment strategies does not allow the expectation that revisions in staging classification will necessarily translate into a better overall outcome, unless over decades. It is controversial whether treatment should necessarily follow a stage change, as stage should not be considered a ‘cook book’ for treatment allocation. The issue is particularly critical for the ‘down-staged’ additional tumour nodules, single zone N2 and T4N0 cases as described before. The analysis of the IASLC database was heavily influenced by surgical cases and pathological staging and cannot necessarily be extrapolated to clinical staging, which has been reported to be inaccurate [56]. Besides, individual patients with more advanced stages but an inherent indolent biological behaviour of their tumour have been reported to profit from more ‘aggressive’ surgical or radiotherapeutic approaches, whilst others with more limited stage will be given symptomatic care for reasons such as poor performance or comorbidity. pT2pN0 tumours with a diameter of 5.5 cm were previously considered pIB and hence not candidates for adjuvant chemotherapy. The same case would now be considered pT2bpN0 and staged pIIA and would be offered adjuvant treatment. We should remember that the data supporting adjuvant chemotherapy after complete resection were generated from trials using the sixth edition of the TNM classification, and that offering adjuvant chemotherapy to ‘reclassified’ stage pIB, pII and pIIIA completely resected cases is therefore not evidence-based [57,58]. A recent pooled analysis of patient cases from two multicentre trials using the size cutpoints of the seventh edition of the TNM classification was unable to identify subgroups of patients who did or did not derive significant benefit from adjuvant chemotherapy after complete resection based on tumour size [59]. Prospective data from large adjuvant chemotherapy trials are necessary before clinical guidelines regarding management of surgically resected node-negative non-small-cell lung cancer (NSCLC) can be updated to reflect the changes introduced.

1.7.

Opportunities

The aforementioned weaknesses and threats offer some challenging opportunities for further research. All unproven descriptors and hypotheses are carried forward for close evaluation in a 25,000-patient prospective database being collected for the future TNM- revision foreseen for 2016 [60].

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The issue of T/pT classification of ground-glass opacities (GGOs) deserves special attention as these are increasingly found at CT-scan screening, with or without a solid component. By histological definition, in-situ adenocarcinoma is defined only for GGOs with a diameter of 6-month interval between sunitinib treatments had a longer PFS with re-challenge (median PFS, 16.5 versus 6.0 months, P = 0.03). Substantial new or increased severity of toxicities was not reported during re-challenge. Finally, newer TKIs have also demonstrated activity in this setting. In a recent phase I/II clinical trial of dovitinib, an inhibitor of multiple-receptor tyrosine kinases, including fibroblast growth factor receptor (FGFr) and VEGF receptor (VEGFr), in patients with mRCC refractory to standard therapies, 8 of 10 patients previously treated with a TKI–everolimus sequence achieved disease control, with one patient experiencing a partial response [10]. This has been convincing enough to launch a large prospective phase III trial comparing sorafenib and dovitinib in patients who have received one TKI and one mTOR inhibitor (ClinicalTrials.gov. NCT identifier: 01223027). This trial, known as the GOLD trial, has completed enrolment and will be reported shortly. Interestingly, first-line PFS, with 6 months taken as cut-off parameter, appears to be an important prognostic factor for survival and thus for the likelihood of benefit of secondand third-line treatments [11].

3. Treatment after TKI (or VEGF inhibitor) followed by axitinib There is currently no evidence that a third TKI after two TKIs has activity, although axitinib has shown some efficacy after sunitinib and sorafenib, with a response rate of 7% and a PFS of 7.1 months in a small number of patients [12]. By contrast, there is level I evidence that everolimus is active after two TKIs, as recognised in the recent ESMO guidelines [4]. In the aforementioned phase III RECORD-1 trial, everolimus was compared with placebo in patients following sorafenib and/or sunitinib [5]. Among patients who received one previous TKI median PFS was 5.4 months versus 1.9 months (HR, 0.32; P < 0.001), and among those who received two previous TKIs median PFS was 4.0 months versus 1.8 months (HR, 0.32; P < 0.001) [13]. Although this might suggest that everolimus is more active when given in second-line than in third-line, it more strongly demonstrates that everolimus is still active when given after two TKIs.

4. Future of treatment beyond second-line in mRCC TKIs as well as mTOR inhibitors have been shown to be active in third-line treatment, depending on the previous sequence,

as discussed above. In the future, several other options might be available. Dovitinib, which is currently in phase III, might become a new standard if the ongoing GOLD study turns out to be positive. Interestingly, this study will also demonstrate whether sorafenib is active in a randomised study after the sequence TKI–mTOR. There is a lot of enthusiasm for targeted immunotherapy, such as anti-PD1 and/or anti-PDL1, in mRCC [14,15]. There is an going phase III evaluating the efficacy of nivolumab (BMS-936558), a T-cell checkpoint (PD-1) inhibitor, after one or two TKIs, in comparison to everolimus (http://clinicaltrials.gov/ct2/show/NCT01668784). Overall survival is the primary endpoint of this study, and this trial will eventually change the standard of care of mRCC treatment if the outcome is positive. Cabozantinib, a Met and VEGF receptor-2 inhibitor, has shown promising activity in mRCC [16]. The activity of this new TKI will be shortly evaluated in a large phase III trial, in comparison to everolimus, after one or two TKIs. Obviously, this treatment might in the future become a very attractive strategy to overcome resistance.

5.

Conclusion

There is evidence that treatment beyond the second line is active in mRCC. Depending on the previous sequence used, both mTOR inhibitors have shown efficacy. New strategies are emerging and might change the landscape, dovitinib being the first drug expected to be incorporated in future guidelines.

Conflict of interest statement None declared. R E F E R E N C E S

[1] Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22:454–63. [2] Manola J, Royston P, Elson P, et al. Prognostic model for survival in patients with metastatic renal cell carcinoma: results from the International Kidney Cancer Working Group. Clin Cancer Res 2011;17:5443–50. [3] Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factortargeted agents: results from a large, multicenter study. J Clin Oncol 2009;27:5794–9. [4] Escudier B, Eisen T, Porta C, et al. ESMO Guidelines Working Group. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23(Suppl. 7):65–71.

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[5] Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449–56. [6] Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931–9. [7] Di Lorenzo G, Buonerba C, Federico P, et al. Third-line sorafenib after sequential therapy with sunitinib and mTOR inhibitors in metastatic renal cell carcinoma. Eur Urol 2010;58:906–11. [8] Blesius A, Beuselinck B, Chevreau C, et al. Are tyrosine kinase inhibitors still active in patients with metastatic renal cell carcinoma previously treated with a tyrosine kinase inhibitor and everolimus? Experience of 36 patients treated in France in the RECORD-1 Trial. Clin Genitourin Cancer 2013;11:128–33. [9] Zama IN, Hutson TE, Elson P, et al. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 2010;116:5400–6. [10] Angevin E, Lopez-Martin J, Lin CC, et al. Phase I Study of Dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor,

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[12]

[13]

[14]

[15]

[16]

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in advanced or metastatic renal cell carcinoma. Clin Cancer Res 2013;19:1257–68. Seidel C, Busch J, Weikert S, et al. Progression free survival of first line vascular endothelial growth factor-targeted therapy is an important prognostic parameter in patients with metastatic renal cell carcinoma. Eur J Cancer 2012;48:1023–30. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 2009;27:4462–8. Calvo E, Escudier B, Motzer RJ, et al. Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptortyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. Eur J Cancer 2012;48:333–9. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455–65. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443–54. Vaishampayan U. Cabozantinib as a novel therapy for renal cell carcinoma. Curr Oncol Rep 2013;15:76–82.

Understanding and managing toxicities of vascular endothelial growth factor (VEGF) inhibitors Manuela Schmidinger

*

Medical University of Vienna, Vienna, Austria

1.

Introduction

Vascular-endothelial growth-factor (receptor) (VEGF)(R)-inhibiting agents – sunitinib [1–3], sorafenib [4,5], pazopanib [2,6], bevacizumab [7,8], axitinib [5] and tivozanib [9,10] – have changed the therapeutic landscape in metastatic renal-cell carcinoma (mRCC). Five out of six agents have been approved for either first-line (sunitinib, pazopanib and bevacizumab + interferon-alpha) or second-line (sorafenib, axitinib) treatment of metastatic or advanced RCC. With these novel strategies, the median overall survival of patients has increased considerably, often, however, at the expense of chronic side-effects. Common treatment-related side-effects include: (1) general symptoms such as fatigue and asthenia, (2) gastrointestinal symptoms such as diarrhoea and stomatitis, (3) skin toxicities, (4) cardiovascular toxicities and (5) a variety of laboratory abnormalities. Some of these side-effects are clinically highly relevant because they may jeopardise the patient’s safety or quality of life, while others may have little clinical relevance. Treating physicians need to be aware of potential side-effects that may occur, how to prevent and/or manage them, and the clinical implications for the ongoing treatment. This is of paramount importance since dose reductions and treatment discontinuations may significantly affect the outcome [11].

2. Incidence of toxicities associated with VEGF inhibitors Toxicities reported from VEGFR inhibitors in mRCC are outlined in Table 1. Among general symptoms, fatigue (and/or asthenia) has been most commonly reported for sunitinib (up to 63% all grades; grade P3: 17%), followed by axitinib (all grades 39%, grade P3: 11%) and sorafenib (all grades 37%; grade P3: 5%). A high incidence of fatigue has also been reported from the combination of bevacizumab + interferonalpha (IFNa). However, the incidence of fatigue appears to be low in patients being treated with bevacizumab alone [12,13]; thus, this side-effect may be attributed to IFNa rather

than bevacizumab. Interestingly, the newest VEGFR–tyrosine kinase inhibitor (TKI) tivozanib appears to have little effect on fatigue levels (all grades: up to 18%, grade P3: 5%). Gastrointestinal side-effects are extremely common in patients on VEGFR–TKI treatment. In particular, sunitinib and axitinib were shown to cause reduced appetite and/or anorexia in up to 34% of the patients. In the case of sunitinib, this may be caused partly by the high incidence of stomatitis and/or dysgeusia (30% and 46%, respectively). Diarrhoea is another frequent gastrointestinal toxicity: high incidences of all grades of diarrhoea were reported from patients on sunitinib (61%), sorafenib (53%), pazopanib (63%) and axitinib 55%, again with quite a favourable profile for tivozanib (22%). The most common skin toxicities caused by VEGFR inhibitors are hand–foot syndrome (HFS), skin- and/or hair-depigmentation and rash. The highest incidence of all grades of HFS has been reported from sorafenib (51%) and sunitinib patients (50%), with a higher grade 3 + 4 HFS incidence in sorafenib patients (16%). Similarly, sorafenib was shown to cause rash in up to 32% of patients (all grades). Hair and/or skin depigmentation is commonly observed in patients on pazopanib (up to 38%) and sunitinib (up to 27%). Among the group of cardiovascular, lung and laryngeal side-effects, hypertension is the most common (up to 46%). Hypertension has been observed with all of these agents and has been considered a fairly reliable biomarker for response, progression-free survival (PFS) and overall survival (OS) [14]. The highest incidence of grades 3 + 4 hypertension has been observed with tivozanib (26%). Cardiac side-effects include congestive heart failure (sunitinib: 13%) and ischaemia or myocardial infarction (sorafenib: 3%; bevacizumab + interferon-alpha 1%). Bleeding events, most commonly epistaxis, have been observed in patients treated with bevacizumab + IFN, sunitinib and sorafenib (33%, 18% and 15%, respectively). While dyspnoea is a common side-effect of mTOR-inhibitors, the incidence is low in patients with VEGFR inhibitors. No direct effect of these agents on lung tissue has been reported so far; thus, the occurrence of dyspnoea might be a secondary event due to lung metastases or

* Address: Manuela Schmidinger, Medical University of Vienna, Vienna, Austria. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.016

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Table 1 – Toxicities reported from phase III trials (%).

(Continued on next page)

oedema as a result of high-grade hypertension or congestive heart failure. In contrast, dysphonia is a common side-effect of new-generation TKIs such as axitinib (31%) and tivozanib (22%). The incidence of grade 3 + 4 myelotoxicity is low with VEGFR inhibitors when compared to classical cancer treatment such as chemotherapy. Nevertheless, multikinase inhibitors,

particularly sunitinib, may induce grade 3 + 4 anaemia (8%), neutropenia (18%), thrombocytopenia (9%) and lymphopaenia (18%). Infections, however, have not been reported yet. Various metabolic and laboratory abnormalities have been shown to occur in patients treated with VEGFR inhibitors. These include renal and electrolyte abnormalities such as creatinine increase (up to 70%), proteinuria (71%), abnormalities

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Table 1 (continued)

in sodium, potassium, magnesium and calcium levels in up to 37%, 50%, 31% and 59%, respectively. In addition, pazopanib, sunitinib and tivozanib in particular were shown to cause increased levels of bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in up to 36%, 60% and 61% of the patients, respectively. In the case of tivozanib, international normalised ratio (INR) and partial thromboplastin time (PTT) abnormalities were also reported (82% and 53%, respectively). Sunitinib, sorafenib and tivozanib were shown to increase amylase and lipase levels in approximately 50% of patients. Finally, the induction of hypothyroidism is an observation that may have been underreported in the pivotal trials; in later analyses, up to 36% of patients was shown to develop hypothyroidism [15]. As with hypertension, the occurrence of hypothyroidism has been linked to a better outcome [15,17].

3. The severity of side-effects and their impact on outcome The occurrence of grade 3 + 4 toxicities, and to some extent also toxicities of lower grades, may tempt clinicians to reduce the dose, or to interrupt or discontinue treatment. Table 2 outlines the incidence of dose reductions and interruptions, the rate and most common reasons for treatment discontinuations, as well as the most common toxicities that have led

to death. Dose reductions occurred in up to 51% of sunitinib patients, 52% of sorafenib patients, 44% of pazopanib patients, 31% of axitinib patients and 14% of tivozanib patients, while no dose reductions of bevacizumab were permitted in the Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial (AVOREN) and CALGB bevacizumab trials. Similarly, dose interruptions and treatment delays were required in 38% of sunitinib patients, 80% sorafenib patients, 62% bevacizumab + IFN patients and 77% of axitinib patients. In contrast, the number of patients with dose interruptions was considerably lower in tivozanib patients (18%). Both dose reductions and treatment interruption may help to prevent or manage treatment-associated side-effects. However, several authors have shown that higher relative dose intensities were associated with better outcome. A pharmacodynamic/ pharmakokinetic analysis including six sunitinib trials revealed that response rates, time to progression and overall survival increased with the mean daily exposure to sunitinib [11]. Similarly, intra-patient dose-escalated sorafenib was shown to exert promising antitumour activity and led to a complete/partial response (CR–PR) rate of 48%, with eight out of 44 patients achieving complete remission [18]. Finally, Rini et al. could demonstrate in a randomised phase II study that axitinib dose titration significantly improved overall response rates when compared to placebo in patients eligible

Table 2 – Dose reductions and treatment discontinuation due to adverse events.

Dose reduction due to AEs (%) Dose interruptions (treatment delays)

Sorafenib [4,5]

Pazopanib [2,6]

Bevacizumab [7,8]

Axitinib [5]

Tivozanib [9,10]

32 51 50 38

13 [4] 52 [5]

44 [2]

Not permitted for bevacizumab

31

8 [9] 13.9 [10]

21 [4] for dermatological events, 80 for GI events [5] 10 [4] 8 [5]

nr

nr [7] 61.7 [8]

77

4 [9] 18 [10]

12 [6] 24 [2]

4

9 [9] 4 [10]

Fatigue, and transient ischaemic attack

nr [9,10]

[1] [2] [3] [1]

8 [1] 19 [2]

Most common reason for discontinuation

Cytopaenia [2]

AEs leading to hospitalisation TX-related death or non-PD related deaths

Renal failure [1] n=1 Gastric haemorrhage [1] n=1 Respiratory failure [1] n = 1 Sudden death [1] n=1

Constitutional [4], gastrointestinal [4], dermatologic [4], respiratory tract symptoms [4] HFS [5], diarrhoea [5], asthenia [5] 34 [4]

Liver events [2]

28 [7] any 19 [7] bevacizumab 23 [8] nr

Nr

nr

nr

nr [9,10]

2 death from cardiac ischaemia/ infarction [4] 2 death [5] from tumour necrosis causing retroperitoneal bleeding and n = 1 GI bleeding

4 [6] ischaemic stroke, hepatic failure, rectal haemorrhage, peritonitis and bowel perforation

2 [7] bleeding events n = 2, GI perforation n = 1, myocardial infarction n = 1 atrial fibrillation n=1 pneumonia n = 1 hepatic failure (history of active hepatitis B) n = 3 [8]

0

n [9]=8/272 ischaemic stroke n = 2, acute coronary syndrome, acute respiratory failure, cerebral vascular accident, hypotension and pulmonary embolism all n = 1 nr [10]

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Discontinuation due to AEs

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Sunitinib [1–3]

nr, not reported.

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for dose titration [19]. The challenge in the management of mRCC patients is to have a balanced approach to maintaining both dose intensity and safety of the patient.

1 1 ( 20 1 3) 1 7 2–19 1

by necrosis with retroperitoneal bleeding and gastrointestinal haemorrhage.

4.4.

4. Reasons for and incidence of dose adjustments and treatment discontinuation by agent 4.1.

Sunitinib

In the final analysis of sunitinib versus IFN-alpha [3], 51% and 19% of sunitinib patients were reported to have required dose reductions or treatment discontinuation, respectively, because of adverse events. Causes of death apart from disease progression included acute renal failure (n = 1), gastric haemorrhage (n = 1), respiratory failure (n = 1) and sudden death (n = 1). In the COMPARZ trial, the most common reason for sunitinib discontinuation was cytopaenia (3%).

4.2.

Pazopanib

In the pivotal pazopanib trial [6] 33% and 4% of patients experienced grade 3 and 4 toxicities, respectively. The adverse event (AE) profile was similar in treatment-naı¨ve and cytokine-pretreated patients, although discontinuation rates because of AEs were higher in the cytokine-pretreated (19%) compared with the treatment-naı¨ve patients (12%). Arterial thromboembolic events occurred in 3% of pazopanib patients – myocardial infarction or ischaemia 2%, cerebrovascular accident 10 mIU/L. In patients with subclinical hypothyroidism (defined as TSH 10 mmol/L) may be acceptable. (2) Should we adjust the dose until toxicity is observed (treating according to toxicity)? In the axitinib dose-titration trial, patients with dose titration and those who did not require dose titration as assessed by the occurrence of hypertension had a better outcome when compared to patients without dose titration [19]. Fig. 1 shows the computed tomography (CT) scans of a female mRCC-patient who did not experience either hypertension (or other dose-limiting toxicities) or remission with axitinib 5 mg bid. Only upon dose adjustment to 7 mg bid did the patient develop hypertension and a reduction in the size of metastasis. These findings suggest that we may consider a potential benefit of the ‘treat to toxicity’ approach. Naturally, such strategies should only be considered in the absence of other dose-limiting toxicities and require careful monitoring. (3) What is the role of agents given to manage the toxicity? Do these agents modify the outcome? We cannot rule out that agents given against the toxicity may have additional benefits against tumour progression. For instance, some antihypertensive agents were shown to exert interesting antitumour properties. Beta-blockers, for example, were shown to induce apoptosis in endothelial cells [191] and have been established as standard of care for infantile haemangiomas [192]. Moreover, several reports have demonstrated that angiotensin II stimulates growth and migration of cancer cell lines and induces angiogenesis through up-regulation of VEGF; interestingly, this effect can be inhibited by angiotensin-receptor blockers (ARBs) [193]. Losartan, an ARB, was shown to stimulate pro-apoptotic signalling pathways in various tumour types [194,195]. Finally, calcium-channel blockers have been shown to reduce the proliferation and migration of glioma cells [196].

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7.

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Conclusions

VEGF inhibitors have substantially improved the outcome of patients with metastatic renal-cell carcinoma. Incidence and severity of side-effects may vary between agents and depend on the mode of action of the chosen drug as well as on individual patient-related factors. Physicians need to be aware of both patient- and agent-related risks that may occur during treatment in order to choose the best individual treatment and maintain the patient’s safety and quality of life. It should be considered that the majority of side-effects are manageable with proactive supportive measures and close monitoring of the patient. Dose reductions, treatment interruptions and discontinuation should be avoided whenever possible.

Conflict of interest

[11]

[12]

[13]

[14]

[15]

Honoraria for lectures or advisory role from Pfizer, Bayer, Roche, Astellas, GSK, Novartis; Research grants from GSK, Pfizer, Novartis.

[16]

R E F E R E N C E S

[18]

[1] Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–24. [2] Motzer RJ, Hutson TE, Reeves J, et al. Randomized open-label phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (MRCC): results of the COMPARZ trial. 2012 ESMO Congress; 2012. [3] Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584–90. [4] Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–34. [5] Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931–9. [6] Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061–8. [7] Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007;370:2103–11. [8] Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol 2010;28:2137–43. [9] Nosov DA, Esteves B, Lipatov ON, et al. Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma. J Clin Oncol 2012;30:1678–85. [10] Motzer RJ et al. Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell

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[162] Wong E, Rosen LS, Mulay M, et al. Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 2007;17:351–5. [163] Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 2012;22:1200–35. [164] Theodossiou C, Skrepnik N, Robert EG, et al. Propylthiouracil-induced hypothyroidism reduces xenograft tumor growth in athymic nude mice. Cancer 1999;86:1596–601. [165] Goodman AD, Hoekstra SJ, Marsh PS. Effects of hypothyroidism on the induction and growth of mammary cancer induced by 7,12-dimethylbenz(a)anthracene in the rat. Cancer Res 1980;40:2336–42. [166] Mishkin SY, Pollack R, Yalovsky MA, Morris HP, Mishkin S. Inhibition of local and metastatic hepatoma growth and prolongation of survival after induction of hypothyroidism. Cancer Res 1981;41:3040–5. [167] Nelson M, Hercbergs A, Rybicki L, Strome M. Association between development of hypothyroidism and improved survival in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 2006;132:1041–6. [168] Hercbergs AA, Goyal LK, Suh JH, et al. Propylthiouracilinduced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: a phase I/II study. Anticancer Res 2003;23:617–26. [169] Trentin AG, Alvarez-Silva M, Moura Neto V. Thyroid hormone induces cerebellar astrocytes and C6 glioma cells to secrete mitogenic growth factors. Am J Physiol Endocrinol Metab 2001;281:E1088–94. [170] Biondi B, Fazio S, Palmieri EA, et al. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 1999;84:2064–7. [171] Mousa SA, O’Connor LJ, Bergh JJ, Davis FB, Scanlan TS, Davis PJ. The proangiogenic action of thyroid hormone analogue GC-1 is initiated at an integrin. J Cardiovasc Pharmacol 2005;46:356–60. [172] Biondi B, Wartofsky L. Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism? J Clin Endocrinol Metab 2012;97:2256–71. [173] Robert C, Soria JC, Spatz A, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005;6:491–500. [174] Yang CH, Lin WC, Chuang CK, et al. Hand–foot skin reaction in patients treated with sorafenib: a clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy. Br J Dermatol 2008;158:592–6. [175] Anderson R, Jatoi A, Robert C, Wood LS, Keating KN, Lacouture ME. Search for evidence-based approaches for the prevention and palliation of hand–foot skin reaction (HFSR) caused by the multikinase inhibitors (MKIs). Oncologist 2009;14:291–302. [176] Brandt J, Briddell RA, Srour EF, Leemhuis TB, Hoffman R. Role of c-kit ligand in the expansion of human hematopoietic progenitor cells. Blood 1992;79:634–41. [177] Gerber HP, Malik AK, Solar GP, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 2002;417:954–8. [178] Gabrilovich D, Ishida T, Oyama T, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998;92:4150–66. [179] Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a

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[180]

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[188]

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pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9:327–37. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003;2:471–8. Kapiteijn E, Brand A, Kroep J, Gelderblom H. Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome. Ann Oncol 2007;18:1745–7. Trinkaus M, Trudeau M, Callum J. Drug-induced immune thrombocytopenic purpura secondary to sunitinib. Curr Oncol 2008;15:152–4. Yoo C, Kim JE, Lee JL, et al. The efficacy and safety of sunitinib in korean patients with advanced renal cell carcinoma: high incidence of toxicity leads to frequent dose reduction. Jpn J Clin Oncol 2010;40:980–5. Schmidinger M, Arnold D, Szczylik C, Wagstaff J, Ravaud A. Optimizing the use of sunitinib in metastatic renal cell carcinoma: an update from clinical practice. Cancer Invest 2010;28:856–64. Donskov F, et al. Neutropenia and thrombocytopenia during treatment as biomarkers of sunitinib efficacy in patients with metastatic renal cell carcinoma (mRCC). Poster presentation at the European Multidisciplinary Cancer Congress; 2011 [abstr. 1141]. Puzanov I, et al. Evaluation of hand–foot syndrome (HFS) as a potential biomarker of sunitinib (SU) efficacy in patients (pts) with metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumour (GIST). Poster presentation at the European Multidisciplinary Cancer Congress; 2011 [abstr. 1444]. Davis Meal. Asthenia and fatigue as potential biomarkers of sunitinib efficacy in metastatic renal cell carcinoma. Poster presentation at the European Multidisciplinary Cancer Congress; 2011 [abstr. 1139]. Kim JJ, Vaziri SA, Rini BI, et al. Association of VEGF and VEGFR2 single nucleotide polymorphisms with hypertension and clinical outcome in metastatic clear cell renal cell carcinoma patients treated with sunitinib. Cancer 2012;118:1946–54. Garcia-Donas J, Esteban E, Leandro-Garcia LJ, et al. Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol 2011;12:1143–50.

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[190] Szmit S, Langiewicz P, Zlnierek J, et al. Hypertension as a predictive factor for survival outcomes in patients with metastatic renal cell carcinoma treated with sunitinib after progression on cytokines. Kidney Blood Press Res 2012;35:18–25. [191] Sommers Smith SK, Smith DM. Beta blockade induces apoptosis in cultured capillary endothelial cells. In Vitro Cell Dev Biol Anim 2002;38:298–304. [192] Menezes MD, McCarter R, Greene EA, Bauman NM. Status of propranolol for treatment of infantile hemangioma and description of a randomized clinical trial. Ann Otol Rhinol Laryngol 2011;120:686–95. [193] Wasa J, Sugiura H, Kozawa E, Kohyama K, Yamada K, Taguchi O. The tumor suppressive effect of angiotensin II type 1 receptor antagonist in a murine osteosarcoma model. Anticancer Res 2011;31:123–7. [194] Gong Q, Davis M, Chipitsyna G, Yeo CJ, Arafat HA. Blocking angiotensin II Type 1 receptor triggers apoptotic cell death in human pancreatic cancer cells. Pancreas 2010;39:581–94. [195] Molteni A, Heffelfinger S, Moulder JE, Uhal B, Castellani WJ. Potential deployment of angiotensin I converting enzyme inhibitors and of angiotensin II type 1 and type 2 receptor blockers in cancer chemotherapy. Anticancer Agents Med Chem 2006;6:451–60. [196] Santoni G, Santoni M, Nabissi M. Functional role of T-type calcium channels in tumour growth and progression: prospective in cancer therapy. Br J Pharmacol 2012;166:1244–6. [197] Bono P, Elfving H, Utriainen T, et al. Hypertension and clinical benefit of bevacizumab in the treatment of advanced renal cell carcinoma. Ann Oncol 2009;20:393–4. [198] Nozawa M, Matsumura N, Yasuda M, Okuda Y, Uemura H. Activity of retreatment with sorafenib for metastatic renal cell carcinoma. In: ASCO Genitourinary Cancers Symposium, February 17–19, Orlando, Florida, 2011 [abstr. 404]. [199] Rixe O. Diastolic blood pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib efficacy in metastatic renal cell cancer (mRCC). J Clin Oncol 2009;27(Suppl.):15s [abstr. 5045]. [200] Feal Bladou. Hypothyroidism and survival during sunitinib therapy in metastatic renal cell carcinoma (mRCC): a prospective observational analysis. J Clin Oncol 2010;28(Suppl.):13 [abstr. e15013]. [201] Baldazzi V, Tassi R, Lapini A, et al. The impact of sunitinibinduced hypothyroidism on progression-free survival of metastatic renal cancer patients: a prospective singlecenter study. Urol Oncol 2012 Sep;30(5):704–10.

Integrating metastasectomy and stereotactic radiosurgery in the treatment of metastatic renal cell carcinoma Axel Bex

*

The Netherlands Cancer Institute, Department of Urology, Amsterdam, The Netherlands

1.

Introduction

In the European Union 60,000 patients are diagnosed annually with renal-cell carcinoma (RCC) [1]. Synchronous metastases are present in up to 30% of patients, with multiple sites affected in 95% [2,3]. Since an additional 40% of those undergoing surgery for localised RCC develop metachronous metastasis, approximately 30,000 patients per year are diagnosed with systemic disease, of which an estimated 7000 have non-clear-cell histology. In a recent population-based analysis, lung metastasis was most frequent at 45.2%, followed by bone at 29.5%, lymph nodes at 21.8% and liver at 20.3% [4]. Adrenal, brain and other locations had a lower frequency. Moreover, it was found that the proportion of patients with multiple metastatic sites was higher in young patients, 16% and 49% of which had brain and bone metastasis, respectively [4].

2.

Rationale of metastasectomy

Selecting appropriate treatment modalities for metastatic RCC remains a challenge. Although objective responses following targeted therapy are frequent, complete remissions occur in only 1–3% [5–7]. Moreover, it has become evident that, despite the most effective drugs in first-line treatment, a ceiling is being reached in median overall survival (OS) which ranges between 9 and 40 months, depending on clinical risk scores [8]. Therefore, together with the occasional durable responses achieved with high-dose interleukin-2, removal of all lesions, when technically feasible, provides the only potentially curative treatment. Traditionally, surgical resection has been the preferred approach (metastasectomy), but recent data on stereotactic radiosurgery (SRS) and ablative techniques indicate that other local non-invasive or less-invasive treatment modalities are a valid alternative to surgery.

However, only a minority of patients with mRCC are candidates for metastasectomy. No reliable data exist on the proportion of patients with mRCC who will be eligible for this approach. It has been estimated that only 25% of patients with metachronous metastasis are suitable candidates for resection of metastatic disease [9,10]. For patients with synchronous metastasis a recent study addressed this issue. A whole-nation study on prevalence and potential resectability revealed that 154 patients (16.9%) had synchronous lung metastases [11]. However, only 11 with solitary lesions were deemed eligible for surgical resection, and only one underwent metastasectomy. In addition, patient selection for this approach is difficult because of the heterogeneous course of metastatic RCC. Metastasis may present at diagnosis or within a year after nephrectomy with curative intent, whereas in others disease-free intervals of more than 20 years have been observed with a slow growth of lesions. In few cases spontaneous regression of metastases has been documented, leading to the concepts of immune modulation [12,13]. Currently, prognosis and management of mRCC depend on a number of clinical factors such as performance status, the length of the disease-free interval, synchronous or metachronous metastasis, as well as the burden of metastatic disease and the number and location of sites involved [14]. One of the most commonly used prognostic models, the Memorial Sloan Kettering Cancer Center (MSKCC) risk score, uses Karnofsky performance status, time from diagnosis to treatment, and serum haemoglobin, calcium and lactate dehydrogenase to categorise patients as being at favourable, intermediate or poor risk [15]. After the introduction of targeted therapy the MSKCC risk score remains a valid tool together with the validated Database Consortium (DCM) model to assess the prognosis of patients with comparable concordances of 0.66–0.65 [8,16,17]. Metastasectomy is associated with survival and clinical benefit across these various risk groups [10,18]. In a

* Corresponding author: Address: The Netherlands Cancer Institute, Division of Surgical Oncology, Department of Urology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel.: +31 20 512 2553; fax: +31 20 512 2554. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.017

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retrospective analysis on 129 patients metastasectomy in the favourable-risk group improved 5-year survival from 36% to 71%, and in the intermediate-risk group from 0% to 38%. When adjusting for risk score, a 2.7-fold increased risk of death remained for patients who did not undergo metastasectomy. Median survival time and 2-year survival rates for lowrisk, intermediate-risk and high-risk patients were 76, 25 and 6 months, respectively, suggesting that only patients with a favourable and intermediate risk live long enough to be candidates for metastasectomy. However, MSKCC and DCM scores were primarily developed to assess prognosis in patients receiving systemic therapies. Other clinical factors which may have prognostic value in metastasectomy are recognised. Patients who are not candidates for metastasectomy are being offered systemic targeted therapy. Following response or substantial downsizing, metastasectomy is occasionally reconsidered in selected individuals to achieve complete resection and even interrupt targeted therapy. This approach is investigational and has not been prospectively studied, but case reports and retrospective series have been published. A case series described three patients after complete resection of liver, lymph node and vertebral metastases following absence of further progression under treatment with sorafenib and sunitinib [19]. Patients remained disease-free after 16, 24 and 29 months. Targeted therapy has been discontinued after complete resection of metastatic lesions. A series included six patients after complete resection of residual metastases in the lungs, iliac bone, skin and thyroid following treatment with sunitinib. The patients remained off treatment for 5–19 months [20,21]. The largest study included 22 patients receiving metastasectomy following targeted therapy [22]. Metastasectomy was performed in the retroperitoneum, lung, adrenal, bowel, mediastinum, bone and brain. Consolidative metastasectomy proved feasible with acceptable morbidity, although it resulted in a significant time off targeted therapy and long-term disease-free interval. However, it is not known whether this was primarily due to the complete resection of metastatic disease, which has been identified as an independent factor associated with prolonged survival, or the combination of surgery and targeted therapy. Ultimately, adequate selection for metastasectomy is of critical importance. If applied appropriately, surgical resection alone or in combination with targeted agents may result in outcome that is superior to systemic therapy alone.

3. General prognostic factors of metastasectomy The bulk of literature on metastasectomy dates back to the last century, when it was observed that patients with solitary resectable metastasis or multiple metastases restricted to one resectable organ site may have a survival benefit in the absence of effective systemic therapeutic options. In the 1930s there was a report of a patient who survived 23 years following pulmonary metastasectomy [23]. In 1978, one of the first series on metastasectomy in 41 patients with solitary lesions in the lungs, pleura, central nervous system and abdomen was published. In patients with complete surgical

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resection, the median disease-specific survival was 27 months, with 59% of the patients alive at 3 years [24]. Several authors concluded similar 3-year and 5-year survival after resection of a solitary lesion [25–27] or observed a significant difference in survival in patients with metachronous and synchronous metastasis [28–30]. In a series involving 179 patients the 5-year survival rate after resection of solitary lesions was 22% for synchronous versus 39% for metachronous metastases [31]. In addition, multiple clinical trials from the cytokine era revealed a strong association of outcome and metastatic sites [32,33]. In a retrospective analysis of 101 patients with resection of a total of 152 metastatic lesions at different organ sites [34], median survival was 28 months for the entire series. Survival was improved after resection of lung metastases when compared to other tumour locations and for patients clinically tumour-free after metastasectomy. Again, the time interval between primary tumour resection and metastasectomy correlated positively with survival. Others have observed similar differences in 5-year survival rates for solitary metastases (56% for lungs, 28% for skin, 20% visceral organs, 18% peripheral bone, 13% brain and 9% axial bone metastases) [31]. One study evaluated 278 mRCC patients to define selection criteria for patients with solitary metastases [35]. On multivariate analysis, factors associated with a favourable outcome were a solitary site and single metastasis, complete resection of the first metastasis, a long disease-free interval and a metachronous presentation. Since then, multiple retrospective series have been published that support these favourable factors [32,36,37] (Table 1). In a recent retrospective analysis of 109 patients who underwent primary tumour resection and at least one metastasectomy for mRCC, the following additional factors were associated with OS [38]; primary tumour stage PT3 stage, Fuhrman grade P3, non-pulmonary metastases, multi-organ metastases and disease-free interval 612 months were negative pretreatment prognostic factors with an accuracy of 0.87. As data from Japan suggest, complete metastasectomy is a favourable prognostic factor independent of race or geographical location [39]. No data from prospective randomised trials on metastasectomy for RCC exist, and decision-making relies on retrospective series. It cannot be excluded that the benefit of metastasectomy is due largely to a lead-time bias based on differences in tumour biology. Patients with solitary and oligometastatic disease and a prolonged metachronous interval are more likely to undergo metastasectomy, while those with extensive metastatic burden, rapid progression and reduced performance will probably never be considered for resection. Perhaps not surprisingly, one series found having an aggressive tumour grade to be the only adverse factor for survival [40]. The significance of tumour heterogeneity and aggressiveness should not be underestimated in the interpretation of data which extend the indication for metastasectomy to multiple sites with the aim of achieving complete resection. Complete resection of multiple lesions has been reported as either a resection performed simultaneously at one or more sites or as repeat metastasectomy of asynchronous recurrences after the first resection.

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Table 1 – Factors associated with a favourable outcome after metastasectomy, including sterotactic radiosurgery (SRS). General and additional reported site-specific factors for the most common sites. Generala

Pulmonary metastasis

Skeletal metastasis

Brain metastasis

Solitary or oligometastatic lesions

2 years Complete resection

Absence of mediastinal lymphnode metastases

Wide excision

RPA class I: 1. Karnofsky PS >70% 2. Age75% decrease of the lesion

Metastases 3 cm 5. Mediastinal/hilar LN 6. Complete resection

ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization; MSKCC, Memorial Sloan Kettering Cancer Center; DCM, Database Consortium model; LN, lymph node. a Recommendations for lymph node, liver, adrenal, pancreatic and thyroid metastasis and other less frequent sites follow the general factors.

Specifically, asynchronous metastases reflect a more benign course of the disease. In selected cases repeat metastasectomy results in exceptionally long survival lasting more than 10 years [41,42]. In a relatively large study of 141 patients with complete resection of solitary metastases, 5-year survival rates after complete resection of second and third metastases were no different when compared to those of the first metastectomy (46% and 44%, respectively, versus a 43% 5-year OS rate) [35]. This supports data from an early retrospective study on repeat metastasectomy which led to improved survival compared to non-surgical treatment of recurrence after first metastasectomy [43]. Recently a large study analysed survival of patients after complete metastasectomy for multiple synchronous metastases at one or more sites [9]. Of 887 mRCC patients, 125 were identified who underwent complete surgical resection of multiple metastases (two to three or more metastases); 52% had resection at two or more sites, including lungs, bone, viscera and other locations. Patients with multiple non-lung-only metastases had a 5-year survival rate of 32.5% with complete resection versus 12.4% without. After controlling for performance status and disease burden, an almost threefold increased risk of death remained for patients with incomplete resection. A scoring algorithm from the same institution to predict survival for patients with clear-cell mRCC suggests that complete resection of multiple metastases was associated with a 50% decrease in the risk of death [14]. It cannot

be ruled out that multiple metastasectomy benefited those patients who would have had a favourable course of disease regardless of surgical intervention. Collectively, these data underscore that careful selection of patients with multiple RCC metastases should be made according to the general prognostic factors (Table 1). A prominent feature of RCC is its ability to metastasise to any anatomical location. Generally, there is little information on how to treat rare sites. In these circumstances factors associated with a favourable outcome after metastasectomy at more frequent sites should be considered for treatment selection (Table 1). Individual decisions have to be taken for each case. However, certain metastatic sites are consistent and more frequently observed. This has led to additional information that may guide treatment decisions. Specific management strategies for the most frequent sites will be discussed in detail. In contrast to traditional surgical metastasectomy, stereotactic radiosurgery (SRS) or ablative techniques have been largely applied to certain metastatic sites [44]. Although treatment of RCC metastases with SRS is gaining ground and is likely to be expanded to multiple anatomical regions, most of the experience stems from brain and bone metastasis and will be discussed below. While ablative techniques are minimally invasive and can cause bleeding and thermal damage, cranial and extracranial SRS involves adverse events such as cough, fatigue, skin rash and local pain. Side effects are generally frequent, but mild (grades I–II in 96%) [45].

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4.

Site-specific strategies

4.1.

Lymph-node metastases

Data on nodal metastasectomy are difficult to interpret. They are not regarded as distant metastasis (M) in the tumournode-metastasis (TNM) classification, and often occur in association with further systemic metastatic sites. As a consequence nodal metastasis can manifest as different disease stages and is generally associated with a poor outcome that resembles that of systemic disease in retrospective series [46]. In few studies are locoregional and distant (mostly mediastinal) lymph-node metastases differentiated. There is evidence that resection of isolated nodes may be beneficial in terms of survival. In fact, isolated lymph-node metastasis is rare. Between 58% and 95% of patients with lymph-node involvement have associated hematogenous metastases [47,48]. Patients with pathological N0 have a 5-year OS of 75%, versus 20% for patients with lymph-node metastases [46,49]. Despite this, patients with single lymph-node metastases and no metastatic disease can potentially be cured by lymph-node dissection (LND) [49]. Regional lymph-node metastases in RCC range from 13% to over 30%. However, the true incidence of solitary nodal metastasis without further systemic disease is unknown. In nephrectomy and autopsy studies single nodal metastases were observed in smaller tumours in 3–4.5% [46,49,50]. At autopsy, anatomical location of lymph-node metastases was unpredictable [51]. The authors found ipsilateral renal hilar lymph-node metastases in 7%, pulmonary hilar lymph-node metastases in 66.2%, retroperitoneal in 36%, para-aortal in 26.8% and supraclavicular in 20.7% [51]. In addition, single metastases in mediastinal, axillary, supraclavicular and iliac lymph nodes without any further metastasis were described [52,53]. In node-positive cases lymph-node dissection was associated with improved survival and a trend towards an improved response to immunotherapy [49]. Patients with regional nodes and distant metastases had significantly inferior survival to those with either condition alone. However, lymph-node status had less impact on survival than primary tumour stage, grade and performance status. [49]. Current guidelines advise that suspicious lymph nodes either at imaging or on palpation should be removed during nephrectomy because LND for clinically positive lymph nodes is associated with improved survival when performed in carefully selected patients [49]. A recent systemic review of the available literature concluded that data from the majority of retrospective non-randomised studies suggest that a possible benefit in terms of OS exists for patients with node-positive disease [54]. In addition, LND at the time of nephrectomy may avoid symptomatic local recurrences. As most clinically suspicious lymph nodes are removed at the time of nephrectomy, few data exist on the management of metachronous regional lymph-node metastases and are often summarised in series reporting on local recurrences [55], but there is a tendency to choose an investigational approach and pre-treat these lesions prior to surgical removal.

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Several cases have been reported with downsizing of nodal metastases following tyrosine kinase inhibitors. Subsequent to sunitinib therapy, complete resection of bulky lymph nodes with encasement of the great vessels not amenable to initial excision was performed in a number of patients with clearcell histology and no evidence of further lesions [56–59]. Downsizing up to 40% was reported following 5–10 cycles. ‘Second-look’ surgery with complete retroperitoneal LND was feasible in all cases. Despite necrosis, viable clear-cell carcinoma was present in all cases.

4.2.

Thoracic metastases

Pulmonary, pleural and mediastinal lymph-node metastases occur frequently in RCC and are found simultaneously in 20–35% of patients [60–62]. Lung lesions are most frequent and have a prevalence rate of 74% in autopsy studies [51]. Metastasis is mostly hematogenous, but direct lymphatic drainage from the kidney into the thoracic duct which subsequently drains into the subclavian vein and pulmonary artery has been proposed [63]. There are many retrospective series on resection of pulmonary metastases, but most of the earlier studies were small [33,35,64–67]. Collectively, recent series with larger patient cohorts observed a 5-year survival rate of 37–54% provided that complete resection of solitary or oligometastatic pulmonary metastases was achieved [9,35,60–62,68–74]. Consistent and robust prognostic factors were identified in multivariate analyses (Table 1). Incomplete resection was associated with a poorer 5-year survival of 0–22% [9,35,60,62,71,74,75], as was the number of pulmonary metastases removed [9,35,62,68,69,75]. Thus, median 5-year survival after complete resection of a solitary lesion was 45.6– 49 months versus 19–27 months after complete resection of multiple metastases [68,69,75]. In a large study a significantly longer median 5-year survival was observed for patients with fewer than seven pulmonary metastases versus those with more than seven metastases (46.8% versus 14.5%) [62]. Furthermore, the presence of lymph-node metastasis was associated with shorter survival [60–62,74]. Despite complete pulmonary metastasectomy, mediastinal lymph-node metastases decreased median survival from 102 months to 19 months [60] and the median 5-year survival rate from 42.1% to 24.4% [62]. A short disease-free interval after nephrectomy or the presence of synchronous metastasis had a poor outcome [35,62,69,71,74,75]. Disease-free interval of > or 0.5 cm [76]. In an attempt to define a prognostic score, 200 consecutive patients with pulmonary metastases were recently evaluated in a single centre [77]. By multivariate anal-

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ysis complete metastasectomy, metastatic size >3 cm, positive lymph-node status of the primary tumour, synchronous metastases, pleural invasion and hilar or mediastinal lymph-node metastases were independent prognostic factors. From these factors the Munich score was developed which discriminates three risk groups with median OS of 90, 31 and 14 months for low, intermediate and high risk, respectively (Table 1). However, some investigators have found no association with the type of resection and survival [68,73]. SRS or ablative techniques may be an alternative to surgical resection in selected patients [45,78]. In a prospective phase II trial of extracranial SRS given to 82 metastases in mRCC, a total of 63 lung lesions were treated [45]; 50% of the patients were MSKCC favourable-risk and 46.7% intermediate-risk. In 21% of the treated sites total regression was observed after 3–36 months, while another 31% showed regression of >50% after 3– 12 months. Median OS was 32 months, suggesting that control and outcome can be achieved similarly to surgical metastasectomy. A recent retrospective analysis including 39 lung lesions suggests that a single fraction equivalent dose (SFED) of P45 Gy is effective for controlling RCC metastases [79]. Isolated mediastinal lymph-node metastasis without pulmonary or other lesions is frequently observed in RCC [80– 82]. This may be a consequence of renal lymphatic vessels which always connect to the origin of the thoracic duct, some directly without traversing any retroperitoneal nodes [63]. Resection of isolated mediastinal and intrapulmonary nodal metastases has resulted in DFS of up to 5 years [83,84]. As these lymph nodes are usually not resected at the time of nephrectomy, these series contain mostly metachronous nodal metastases. As already mentioned, concurrent mediastinal lymph-node and lung metastases have a poorer prognosis [60–62]. These studies provide information on the potential prevalence of lymph-node metastases in patients with pulmonary metastatic disease which was 20–35%. With a median OS of 18 months [115]. In summary, adrenalectomy for isolated metachronous ipsilateral and contralateral adrenal metastasis is recommended because it is associated with long-term survival in individual patients. Ablative percutaneous techniques may be an alternative to open or laparoscopic adrenalectomy [117].

5.3.

Pancreatic metastases

Pancreatic metastases of RCC are relatively infrequent but have been described in 411 patients in 170 publications [118]. A systematic literature search reported the clinical outcome of pancreatic RCC metastases [118]. Of the metastases, 321 were treated surgically and 73 non-surgically. In the metastasectomy group 65.3% of the lesions were solitary and symptomatic in 57.4%. Following metastasectomy, 2-year and 5-year diseasefree survival was 76% and 57%, respectively. Interestingly, the 2- and 5-year OS rates were 80.6% and 72.6%. Further extrapancreatic disease had no impact on OS in the metastasectomy group. Surprisingly, the time to pancreatic metastasis and the number of pancreatic lesions were not associated with a worse outcome. As expected, patients with unresected pancreatic disease had a significantly shorter 2- and 5-year overall survival rate of 41% and 14%, respectively. These data suggest that metastasectomy may be beneficial in patients in whom the pancreas is the only metastatic site and who are fit enough to undergo pancreatic surgery. In-hospital mortality after pancreatic metastasectomy was 2.8%, and a significant number of patients underwent extensive surgery (pancreaticoduodenectomy in 35.8% and total pancreatectomy in 19.9%). In view of the retrospective quality of the data and the significant surgical morbidity, patients with a short time to pancreatic metastasis following nephrectomy may be best treated with systemic therapy first.

5.4.

Brain metastases

Brain metastasis is observed in 2–17% of patients with RCC, and is readily diagnosed by symptoms in more than 80% of cases [119–121]. If left untreated, median survival is poor (3.2 months) [122]. After the introduction of SRT, indications for craniotomy have been largely abandoned except for lesions >2–3 cm, rapid onset of symptoms and in cases of large lesions with midline shift [123–125]. Because of their relative paucity, therapeutic strategies for RCC brain metastases have often been evaluated together with cerebral lesions of various primary tumours. Generally, selection of patients for therapy of brain metastases, regardless of the primary tumour site, involves assessment of performance status, extracranial tumour load and the course of the disease, as summarised in the Radiation Therapy Oncology Group (RTOG) recursive partition analysis (RPA) [126]. Unfortunately, the majority (70–80%) of patients with RCC brain lesions belong to RPA class II – Karnofsky score (KS) >70%, further extracranial metastases – who have a poor median survival of 4.2 months [124,127]. In another study, including 4295 patients, significant prognostic factors for RCC brain metastasis were KS performance status and number of brain metastases [128]. Those with a KS of 90–100% and a single brain metastasis had a median OS of

1 1 ( 20 1 3) 1 9 2–20 3

14.8 months versus 3.3 months for those with a KS 75% decrease in metastasis volume. It has been argued that survival rates after SRS are inferior to those after craniotomy, but the size of the retrospective series involving patients with RCC brain metastases, and the fact that more patients with a long metachronous interval and fewer brain metastases were candidates for craniotomy [132,137], do not allow a direct comparison.

5.5.

Thyroid metastases

The thyroid gland is infrequently involved, and the first cases were reported in the 1940s [138]. The largest retrospective study evaluated 45 resections of solitary thyroid metastases at 15 different centres [139]. The 5-year overall survival rate was 51%. Prognosis was significantly poorer in patients >70 years of age, but no other factors were established. There was a striking coincidence of thyroid and pancreatic metastases (31%). Another group reported on seven patients with solitary RCC metastases in the thyroid and a median OS after thyroidectomy of 38.1 months [140]. In a clinicopathological study of 36 cases, 64% had documented previous evidence of RCC as

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1 1 ( 2 0 1 3 ) 1 9 2 –2 0 3

Table 2 – Median overall survival and 5-year survival rates after surgical complete resection or stereotactic radiosurgery (SRS) of solitary or oligo metastasis at various sites. Metastatic site

Patient numbers

Median OS

5-Year survival rates (%)

Pulmonary

48–200

37.2–54

Liver Bone Brain

31–68 9–38 11–138

Adrenal (ipsi- and contralateral) Pancreas Thyroid

5–30 321 (review) 7–45

Munich I: 90 months Munich II: 31 months Munich III: 14 months After SRS: 32 monthsa Not reported Not reported RPA I: 14.8 months RPA II: 4.2 months After SRS: RPA I: 24.2 months RPA II: 9.2 months 8–70 months Not reported 38.1 months

38.9–62.2 40–55 12–18

51–100 57 51

RPA, recursive partition analysis. 97% Memorial Sloan Kettering Cancer Center (MSKCC) favourable and intermediate.

a

long as 21.8 years before the thyroid lesion developed (mean, 9.4 years). After a mean follow-up of 9.1 years, 36% were alive or had died without evidence of disease [141].

6.

Conclusion

Only few and selected patients, especially those with solitary metastases at single-organ sites, may benefit from metastasectomy. Consistently, survival benefit and even cure have been reported after complete surgical resection and SRS (Table 2). However, available data specifically related to RCC are from retrospective non-randomised studies. Therefore it remains unresolved whether the observed survival benefit is a consequence of surgical intervention or a selection of patients with more benign tumour biology who, owing to a mild clinical course, were considered for metastasectomy. The best outcome has been observed after resection of metachronous solitary or oligometastases in the lung, but similar survival rates were reported for other sites, including liver, pancreas, bone and even multiple sites, provided that complete resection was achieved. Despite consistent prognostic factors associated with a favourable outcome following metastasectomy, no general therapeutic guideline can be given. Careful patient selection is paramount, and the decision to resect metastases has to be taken for each site and each individual patient. Performance status, risk profiles, patient preference and alternative techniques to achieve local control, such as SRS or ablation, will have to be considered. After the introduction of targeted therapy, more patients with metastatic RCC may become candidates for complete surgical resection; pretreatment and multimodality concepts integrating medical and surgical treatments are being investigated.

7.

Conflict of interest statements

A.B. has taken part in advisory boards of Pfizer, Bayer, GSK and Novartis. A.B. is the PI of the EORTC SURTIME trial which is in part supported by an educational grant from Pfizer.

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[113] Lau WK, Zincke H, Lohse CM, et al. Contralateral adrenal metastasis of renal cell carcinoma: treatment, outcome and a review. BJU Int 2003;91:775–9. [114] Dieckmann KP, Wullbrand A, Krolzig G. Contralateral adrenal metastasis in renal cell cancer. Scand J Urol Nephrol 1996;30:139–43. [115] Kessler OJ, Mukamel E, Weinstein R, et al. Metachronous renal cell carcinoma metastasis to the contralateral adrenal gland. Urology 1998;51:539–43. [116] Onishi T, Ohishi Y, Goto H, Suzuki H, Asano K. Metachronous solitary metastasis of renal cell carcinoma to the contralateral adrenal gland after nephrectomy. Int J Clin Oncol 2000;5:36–40. [117] Welch BT, Atwell TD, Nichols DA, et al. Percutaneous imageguided adrenal cryoablation: procedural considerations and technical success. Radiology 2011;258:301–7. [118] Tanis PJ, van der Gaag NA, Busch OR, van Gulik TM, Gouma DJ. Systematic review of pancreatic surgery for metastatic renal cell carcinoma. Br J Surg 2009;96:579–92. [119] Levy DA, Slaton JW, Swanson DA, Dinney CP. Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma. J Urol 1998;159:1163–7. [120] Ljungberg B, Alamdari FI, Rasmuson T, Roos G. Follow-up guidelines for nonmetastatic renal cell carcinoma based on the occurrence of metastases after radical nephrectomy. BJU Int 1999;84:405–11. [121] Sandock DS, Seftel AD, Resnick MI. A new protocol for the followup of renal cell carcinoma based on pathological stage. J Urol 1995;154:28–31. [122] Decker DA, Decker VL, Herskovic A, Cummings GD. Brain metastases in patients with renal cell carcinoma: prognosis and treatment. J Clin Oncol 1984;2:169–73. [123] Muacevic A, Kreth FW, Horstmann GA, et al. Surgery and radiotherapy compared with gamma knife radiosurgery in the treatment of solitary cerebral metastases of small diameter. J Neurosurg 1999;91:35–43. [124] Muacevic A, Kreth FW, Mack A, Tonn JC, Wowra B. Stereotactic radiosurgery without radiation therapy providing high local tumor control of multiple brain metastases from renal cell carcinoma. Minim Invasive Neurosurg 2004;47:203–8. [125] Shuch B, La Rochelle JC, Klatte T, et al. Brain metastasis from renal cell carcinoma: presentation, recurrence, and survival. Cancer 2008;113:1641–8. [126] Gaspar LE, Scott C, Murray K, Curran W. Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys 2000;47:1001–6. [127] Cannady SB, Cavanaugh KA, Lee SY, et al. Results of whole brain radiotherapy and recursive partitioning analysis in patients with brain metastases from renal cell carcinoma: a retrospective study. Int J Radiat Oncol Biol Phys 2004;58:253–8. [128] Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multiinstitutional analysis of 4259 patients. Int J Radiat Oncol Biol Phys 2010;77:655–61. [129] Wronski M, Maor MH, Davis BJ, Sawaya R, Levin VA. External radiation of brain metastases from renal carcinoma: a retrospective study of 119 patients from the M. D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys 1997;37:753–9. [130] Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al. The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 1994;29:711–7.

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[131] Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993;33:583–90. [132] Wronski M, Arbit E, Russo P, Galicich JH. Surgical resection of brain metastases from renal cell carcinoma in 50 patients. Urology 1996;47:187–93. [133] Marko NF, Angelov L, Toms SA, et al. Stereotactic radiosurgery as single-modality treatment of incidentally identified renal cell carcinoma brain metastases. World Neurosurg 2010;73:186–93. [134] Mori Y, Kondziolka D, Flickinger JC, Logan T, Lunsford LD. Stereotactic radiosurgery for brain metastasis from renal cell carcinoma. Cancer 1998;83:344–53. [135] Sheehan JP, Sun MH, Kondziolka D, Flickinger J, Lunsford LD. Radiosurgery in patients with renal cell carcinoma metastasis to the brain: long-term outcomes and prognostic factors influencing survival and local tumor control. J Neurosurg 2003;98:342–9. [136] Kim WH, Kim DG, Han JH, et al. Early significant tumor volume reduction after radiosurgery in brain metastases

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from renal cell carcinoma results in long-term survival. Int J Radiat Oncol Biol Phys 2012;82:1749–55. Badalament RA, Gluck RW, Wong GY, et al. Surgical treatment of brain metastases from renal cell carcinoma. Urology 1990;36:112–7. Linton RR, Barney JD. Metastatic hypernephroma of the thyroid gland. Surg Gynecol Obstet 1946;83:493–8. Iesalnieks I, Winter H, Bareck E, et al. Thyroid metastases of renal cell carcinoma: clinical course in 45 patients undergoing surgery. Assessment of factors affecting patients’ survival. Thyroid 2008;18:615–24. Benoit L, Favoulet P, Arnould L, et al. Metastatic renal cell carcinoma to the thyroid gland: report of seven cases and review of the literature. Ann Chir 2004;129:218–23. Heffess CS, Wenig BM, Thompson LD. Metastatic renal cell carcinoma to the thyroid gland: a clinicopathologic study of 36 cases. Cancer 2002;95:1869–78.

Introduction

Mood disorders in cancer patients O. Husson Tilburg University, Faculty of Social Sciences, Tilburg, Netherlands

‘If I can’t feel, if I can’t move, if I can’t think, and I can’t care, then what conceivable point is there in living?’ (Kay Redfield Jamison, An Unquiet Mind: A Memoir of Moods and Madness) Mood is a person’s subjective emotional state. According to the DSM-IV the term mood disorder is used for a group of diagnoses where the primary symptom is a disturbance in mood, or in other words the experience of an inappropriate, exaggerated or limited range of feelings. Mood disorders can mainly be divided into two groups: (1) depressive episode(s) characterised by feelings of sadness, hopelessness, helplessness, guilt, suicidal thoughts, fatigue, appetite changes, concentration problems and troubles engaging in daily living tasks; (2) manic or hypomanic episode(s) characterised by feelings of grandiosity, extreme energy and heightened arousal. Several treatment options are available for mood disorders – e.g. medication, cognitive and/or behavioural therapy – depending on the severity and the evaluation of the health-care provider. Several studies have shown that mood disorders are common in patients with cancer. In a meta-analysis, the point prevalence of major depression was about 16% and that of anxiety was 10% [1]. The exact causes of mood disorders are largely unknown, but it is hypothesised that an imbalance in neurotransmitters is likely to play a role. The mood disorder can be triggered by the cancer diagnosis on its own, or it can be treatment-induced in cases where the aetiology can be found in the physiological effect of a psychoactive drug or chemical substance. These articles provide an overview of the most common mood disorders among cancer patients. First, Dr. Dauchy will

discuss the prevalence, predictive factors and treatment options of depression, one of the most under-diagnosed and inadequately treated mood disorders among cancer patients. Second, Professor Caraceni will introduce drug-associated delirium, an altered state of consciousness with reduced awareness of self and the environment, which may go hand in hand with the inability to think and talk clearly and rationally, hallucinations, disorientation and cognitive impairment. Third, Dr. Die Trill will discuss anxiety, one of the most frequently reported reactions to a cancer diagnosis, which may persist throughout the cancer continuum. In addition, she will shine her light on sleep disorders, which are frequently associated with psychological disorders. Finally, Dr. Schagen will describe the chemotherapy-related changes in cognitive functioning, which can result in diminished functional independence and can last throughout the survivorship period.

Conflict of interest statement None declared.

R E F E R E N C E

[1] Mitchell AJ, Chan M, Bhatti H, et al. Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview-based studies. Lancet Oncol 2011;12:160–74.

1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.005

Depression in cancer patients S. Dauchy a b c

a,* ,

S. Dolbeault b, M. Reich

c

Gustave Roussy, Villejuif, France Institut Curie, Paris Cedex, France Centre Oscar Lambret, Lille, France

1.

Introduction

Depression is frequent in cancerology. Despite its clear impact on patients, it continues to be under-diagnosed and inadequately treated. There are many reasons for this, ranging from the underestimation of depressive symptoms by clinicians, their widespread presence in the context of cancer, the entanglement of depressive symptoms with those associated with the cancer and its treatment, or, indeed, the difficulty of clinicians in exploring emotional symptoms [1,2]. Beyond the fact that depression causes mental suffering that is not taken into consideration, even though it can be extremely intense in nature, this situation has a major impact on both morbidity and mortality through a number of different mechanisms [3,4]: • • • • • • • •

Deterioration of quality of life [5]. Increased sensitivity to pain [6]. Difficulties observing treatment [7]. Difficulties communicating with carers, friends and family. Significant burden placed on close relatives [8]. Increased risk of suicide [9]. Longer periods of hospitalisation [10]. Reduced expectation of survival [11].

Depression also results in additional medico-economic costs, the extent of which we are only just beginning to understand [12,13]. There is also a risk of over-treatment, with antidepressants being systematically administered for what may only be an intense feeling of sadness, which may nevertheless be appropriate in the context and temporary in duration.

to the variability of the clinical forms of depressive disorders – major depressive episode (MDE), dysthymia, adjustment disorders with depressed mood, etc. – and the way in which the diagnosis is performed: clinical interview, questionnaires or self-report questionnaires which may be specific to depression (BDI, CES-D and Zung scale) or more general (HADS, POMS and SCL-90 etc.), variability of the cut-offs, etc. The figures also vary depending on the sample and, in particular, on the patient’s medical status, type of cancer, location, stage, treatment during or after cancer, etc. There may also be a bias associated with the selection of the patients (patients who have agreed to a clinical psychiatric assessment, convenience sample etc.). On average, studies report a prevalence of MDE of 5–10%, two to three times higher than that in the general population. In a recent meta-analysis of 70 studies (n = 10,071) conducted by Mitchell et al. [14], the prevalence of depressions of all types (ICD, DSM criteria) was 16.3%, with the prevalence of MDE reaching 6%. The corresponding values rose to 24.6– 29% and 14.3–16.5% in the analysis of 24 studies (n = 4007) of palliative-phase patients. The way in which depressive disorders develop during the period of cancer care is still poorly understood because of a lack of longitudinal studies. A depressive episode may be isolated or may have been preceded by other such episodes. In this latter case, the disorder is a recurrent unipolar depression. The patient’s antecedents may also include one or more phases of hypomanic or manic excitation, or he or she may have presented a hypomanic reaction when under antidepressants. In this case, a bipolar mood disorder is probable. Referral to a psychiatrist will then be necessary for diagnosis and identification of the relevant treatment.

2. What is the prevalence of depression in cancerology?

3.

Although depression is frequently observed in cancerology, the figures reported by the various related studies differ owing

Some of the risk factors for depression are known and must be identified at an early stage [15,16].

What are the predictive factors?

* Corresponding author. Tel.: +33 1 42 11 46 30. E-mail address: [email protected] (S. Dauchy). 1359-6349/$ - see front matter Copyright  2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.006

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• •

•

•

•

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Personal risk factors:

•

Recent personal history of negative or stressful life events (bereavement, succession of losses). Personal psychiatric antecedents (depression, suicide attempt, drug addiction and alcoholism) or familial antecedents (depression, suicide attempt and suicide) [17]. Personality traits – tendency not to express one’s emotions, tendency to consider life events as uncontrollable and inevitable, low self-esteem and poor emotional support and tendency to pessimism [18,19]. Unlike the data obtained in the general population, the most recent meta-analysis conducted by Mitchell et al. [14] suggests that gender is not predictive, possibly owing to the weight of the factors associated with the cancer itself. The role of age (5% of body weight), or increase or decrease in appetite. Insomnia or hypersomnia. Psychomotor agitation or retardation. Fatigue or loss of energy. Diminished concentration or indecisiveness.

A change in character with the appearance of irritability or aggressiveness that is inconsistent with earlier behaviour is also possible. If five symptoms from the above list, including mental pain and/or absence of pleasure, are present then the patient is very probably depressed, and antidepressant treatment is recommended. If not, the patient is exhibiting either a temporary depressive reaction (if the criterion of persistence over time is not

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met) or an adjustment disorder with depressed mood (if insufficient symptoms are present: for example, sadness on its own without feelings of worthlessness, sleep disorders or anhedonia). Antidepressants are not indicated a priori. Another difficulty affecting the diagnosis of depression is associated with the distinction between its somatic manifestations (fatigue, anorexia and/or loss of weight, cognitive or sleep disorders, loss of libido) and the physical symptoms associated with the cancerous disease or its treatment [30]. A number of ways of overcoming this difficulty have been described: •

• •

An inclusive approach in which all the symptoms are taken into account, irrespective of whether or not they are attributable to the cancer (which clearly leads to a risk of over-diagnosis). An exclusive approach in which the somatic symptoms are systematically excluded from the diagnostic criteria. A substitution method in which these very same somatic symptoms are replaced by affective substitute symptoms [31].

When the exclusive and substitution approaches are used, the risk that the diagnosis may be underestimated is high, in particular in the case of patients who conceal or repress their emotions. In practice, all manifestations that are not clearly linked to another cause (physical or iatrogenic causes) should be considered as contributing to the diagnosis of the depressive syndrome. The chronology of the disorders is particularly useful in this context. It is therefore necessary to pay special attention to the cognitive and affective symptoms that are not directly linked to the somatic state, together with all their possible nuances: •

• • •

•

Self-devaluation and a painful vision of the past: feelings of uselessness, worthlessness and guilt (invasive, generalised). Loss of interest and pleasure: affective anaesthesia, indifference. Feeling of worthlessness coupled with feelings of helplessness and hopelessness. Desire for death and thoughts of suicide must be systematically explored; far from inducing suicidal behaviour, putting such ideas into words is an opportunity for the patient to become aware of their pathological nature and their link, not to a rational perception of reality, but to his or her own depressive suffering. Pathological pessimism.

A final difficulty lies in the fact that patients rarely spontaneously express those depressive symptoms that are primarily purely affective in nature (emotional withdrawal, for example), and that depressive symptoms themselves (psychomotor retardation, social withdrawal and shame) and lack of knowledge or minimisation of depressive symptoms lower this expression. Simple, open questions should therefore be favoured during the interview (‘How’s your mood? And everyday life? Are there some good times? etc.’).

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It is important to avoid moralizing phraseology (‘face up to’, ‘keep going’) and closed questions (‘Are you in a good mood? Are you coping?’) which risk blocking the expression of the experienced feelings and increasing the sensation of guilt due the patient’s perception of his or her depressed state. The availability of the carer, whether verbal or non-verbal, is vital for facilitating emotional expression. The diagnosis must take into account the time of the assessment. The assessment of depressive symptoms is difficult during the days immediately following the announcement of bad news or in the case of an evolutive, uncontrolled somatic symptomatology, in particular if this is associated with the experience of pain. In such cases, the patient should be reassessed at a distance or after the symptoms have been treated. Finally, the idea of a break with earlier behaviour is also important. The clinician must remain attentive to changes in the patient’s functioning, whether this is revealed by the patient or his or her friends and family. Helping patients become aware of this change may also make it easier for them to grasp the pathological nature of their condition.

5.

How to screen for depression in cancerology?

Simple, validated tools can be used, and the aim for screening purposes is to select short tools taking no more than 5 min to complete. A recent review of the various potential tools for the screening of distress undertaken by Mitchell [32,33] identified 35 short tools for the screening of depression, consisting of 1–14 items. Although some of these specifically assess depression and have been validated for use in cancerology, most of them were not specifically designed for administration to patients suffering from a somatic pathology. This fact can be problematic when the deterioration of the patient’s general condition aggravates scores on items that evaluate the respondent’s somatic state; this criticism has been made with regard to the BDI (Beck Depression Inventory), for example [34]. Others, such as HADS (Hospital Anxiety and Depression Scale), assess emotional distress at a more general level but have the advantage of excluding somatic items. The following tools have been validated for use with cancer patients: single verbal item, PHQ1, PHQ2 (and PHQ2 + help question), two verbal items BCFD (Bried Case Find for Depression), Edinburgh Postnatal Depression Scale (EPDS, and Brief EPDS), Hornheide Screening Instrument (and Hornheide Short Form), General Health Questionnaire 9, BDI Short Form, HADS (and HADS depression subscale). The sensitivity and specificity of the different scales vary as a function of the cut-offs used and of the patient clinical condition. None of the tools used today can be claimed to be irrefutably preferable to any other. It should nevertheless be noted that in most studies the sensitivity and specificity of ultra-short tools (consisting of just one or two questions, ‘low mood’ and ‘loss of interest or pleasure’) have been found to be at least as good as those of longer tools. In the metaanalysis of screening and case-finding tools for depression in cancer conducted by the Depression in Cancer Care consensus group [29], 56 diagnostic validity studies (n = 10,009)

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were reviewed. For case-finding, one stem question, two stem questions and the BDI-II all had level 2 evidence. For screening, two stem questions had level 1b evidence. As they are highly acceptable, the stem questions are thus recommended (grade B recommendation). For every 100 people screened, the two questions would accurately detect 18 cases in advanced cancer settings (one missed and seven falsely identified), and 17 in non-palliative settings (two missed, and 11 falsely identified as cases). By contrast, clinical appraisals that are not guided by at least one or two questions are not recommended, in particular if the clinicians are not trained [35]. In practice, it is important to remember that the diagnosis of depression is too complex for any screening tool, used in isolation, to be able to provide absolute certainty. Nevertheless, their use is recommended and can be incorporated within a more global assessment of the patient’s symptoms (as in the case of the Edmonton Symptom Assessment System, ESAS), supportive care needs or expectations [32]. The main value of these tools – and in particular of those which permit an assessment based on two questions – is that they make it possible to identify with a high degree of certainty those patients who are not depressed, and consequently focus the efforts of the oncologist, carer or psychologist/psychiatrist on obtaining a more in-depth assessment of those individuals who have screened positively. However, systematic screening for depression has not as yet proved its effectiveness in significantly improving patients’ psychological outcomes [36]. Far from casting doubt on its usefulness, this fact emphasises the vital need to include this type of screening in an overall treatment process that extends through to the proposal and acceptance of appropriate pharmacological and/or psychotherapeutic care.

6.

Depression and the risk of suicide

Despite the variability that can be found in the literature, owing to problems of both methodology and definition, it is possible to estimate the risk of suicide in the oncological context at 1.95–2.8 times higher than in the general population [9,37]. The wish to die is present in 17% of patients in an advanced phase of cancer. Certain suicide risk factors are known [20,37] • • • • • • • • •

Poorly controlled symptoms (pain, fatigue, etc.). Masculine gender (relative risk of 1.7 in men and 1.4 in women compared with the general population [38]). Disclosure phase (first year following the diagnosis) [37]. Site of the tumour (head and neck, lung, gastrointestinal, brain tumours [9]). Existence of a psychopathological disorder (depression, hopelessness, delirium). Familial antecedents of suicide and/or psychiatric illness, previous personal suicide attempts. Pathological impulsivity (personality disorder). Substance abuse (alcohol etc.). Recent loss (bereavement, for example).

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•

Situation of autonomy [1].

hopelessness,

loss

of

control

or

It is interesting to note that most of these factors are found in cases where patients ask to accelerate their death (hastening death requests are associated at a significant level with depressive states, hopelessness, low level of social support, very poor physical condition and a lower level of recourse to spirituality) [1]. Whenever patients make this type of request, one should systematically and carefully search for an emotional disorder that may indicate pathological suicidal ideation.

7.

Treatment plan and overall patient care

The treatment of depression has to start at an early stage [39]. It can take a long time to make patients aware of the psychological nature of their difficulties, encourage them to request a psychological consultation or to accept the prescription of psychotropic or, in particular, antidepressant medicaments. The more intense the psychological distress the longer this delay may be. It is the systematic attention paid by clinicians to their patients’ psychological states that permits early diagnoses and the effective elaboration of an appropriate treatment plan. The treatment of depression must form part of an overall care context. First of all, it is necessary to take account of the patient’s somatic condition, the associated symptoms and any comorbidities that may be present (pain, fatigue and sexual problems). It is not possible, for example, to treat depression in patients with uncontrolled pain [40]. To start from the patients’ expectations – for example, by identifying with them the symptom that causes them the greatest distress, or discussing what they can expect from treatment – may help them to accept depression treatment. Certain patients, for example, who can no longer themselves perceive the loss of the ability to experience pleasure or are unaware of their psychomotor retardation, may primarily complain of sleep-related problems. An initial prescription of drugs that are effective in combating these sleep disorders will encourage subsequent adherence to therapy. The patient’s habitual mode of psychological functioning may also help the clinician guide him or her towards appropriate psychotherapeutic support. It is also necessary to try to identify the representations associated with depression, antidepressant treatments or psychotherapies, together with any possible prior intolerance of antidepressant treatment. Patients must be given information about their socio-professional circumstances and psychosocial resources (family, work and environment). What psychosocial resources can they count on in their family or professional environments? And, conversely, what strains or obligations are imposed on them? The next step is to check the level of information that patients possess regarding the cancer for which they are being treated, their understanding of the treatment plan and their adherence to it. The quality of the cooperation between the

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psychologist or psychiatrist, on the one hand, and the oncologist, on the other, may if necessary make it possible to revisit any information that has been inadequately understood. Finally, therapeutic care for mental distress, in particular when drug-based treatments are used, must always be initiated by a stage during which the psychological nature of the disorders is explained and clear information about the prescribed psychotropic drug – its purpose and any possible side effects (risk of dependence associated with benzodiazepines or hypnotic substances, for example) – is provided. Nevertheless, given the specific symptoms that characterise depressive states, it can sometimes be difficult to secure the commitment of depressed patients to a course of treatment, in particular when they find it difficult to acknowledge the pathological nature of their condition or when the loss of hope or confidence in the future is significant. Memory and attention disorders may aggravate a patient’s reluctance to agree to psychotropic treatment and impair compliance with it, especially given that the anxiety that is frequently felt at the start of treatment may be associated with an increase in the real or feared side effects. The discussion of the diagnosis is therefore the first step in the administration of treatment. The information provided to depressed patients enables them to better understand the nature of their distress and retain their independence. The empathy shown by carers in response to their psychological distress also constitutes an initial vital and beneficial experience for depressed patients, who often feel isolated due to the shame and guilt they experience (and withdraw themselves both from their friends and family and from their oncological team) [41]. To treat major depressive episodes it is necessary to prescribe both an antidepressant and, in certain cases, a course of psychotherapeutic care [1,15] or, at the very least, to ensure the availability of psychosocial support to facilitate adherence to treatment [42].

8. When and antidepressant?

how

to

prescribe

an

It is appropriate to prescribe an antidepressant for all major depressive episodes. This prescription does not always have to be accompanied by treatment by a psychiatrist except in the case of depression affecting patients with bipolar mood disorders who should be referred to a psychologist for diagnosis and treatment. In a recent Cochrane review [43] it was established that antidepressants outperform placebo level among patients with somatic diseases (OR 2.33, IC 1.8–3, P < 0.00001). This finding redresses a scientific shortcoming in the field of cancerology: in 2008, only 20 studies of the effectiveness of antidepressants had been conducted in this field and none of them had reached a sufficient level of proof [2]. However, we still need to gain a better understanding of the rationale underlying the pathogenesis of depression in the cancer field and, in particular, its links with the immune and inflammatory mechanisms.

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Table 1 – Families of antidepressants. Family SNRI : Venlafaxine, minalcipran and duloxetine Nassa : Mianserine and mirtazapine Melatonihergic : Agomelatine Others : Tianeptine A preventive treatment is not recommended except in some very specific cases, as in e.g. depression induced by high-dose interferon alpha [44]. Generally speaking, SRIs (serotonin reuptake inhibitors) (Table 1) tend to be the first drugs to be prescribed in the field of cancerology [45]. There is no reason to consider the effectiveness of any antidepressant to be formally superior to that of any other [46–48]. When administered at antidepressant dosage (which is considerably higher than the antalgic dosage), tricyclics (Table 1) are difficult to handle and should be reserved for more complex cases. Escitalopram might be the medicament with the best effectiveness-to-tolerance ratio among patients who have no contraindication for this drug [45]. Furthermore, the choice of an antidepressant is specific to the patient and is determined by individual factors: the side effects of the drug, the patient’s tolerance to it (which includes potential side effects in combination with other drugs being co-administered or that might be used in the future), reactions to earlier treatments, and the patient’s preferences [49]. In particular, it is especially important to make sure that no potential iatrogenics exacerbate the somatic or non-somatic difficulties that are already present (for example, sexual difficulties or asthenia). In the majority of cases, monotherapy is the rule; to combine two antidepressants is a priori pointless and potentially dangerous. Although exceptions exist, such prescriptions should only be made by specialists. Accompanying prescriptions – for example of anxiolytic or hypnotic drugs – should be restricted. These may be prescribed at the start of treatment but clinicians should attempt to reduce or eliminate them as treatment progresses. The fact that a period of 2–3 weeks is required before any effect can be observed must be explained to the patient who must also be alerted to the possibility of undesirable side effects. It is important to remain vigilant with regard to the aggravated vulnerability of cancer patients (specific metabolic characteristics, associated treatments) and remain attentive to the identification of secondary effects which sometimes may not be easy to detect in a somatic context. Tolerance to antidepressants varies depending on the drug in question, and tolerance to tricyclic antidepressants is often poor since these drugs frequently produce side effects (orthostatic hypertension, weight gain, sedation, irregular heartbeat, confusion, epilepsy and potentially fatal in the event of an overdose), which is why they are not administered as the first line of treatment. The toxicity of serotonin reuptake inhibitors is less serious and is often restricted to self-limiting disorders (headaches, gastrointestinal disorders). All drugs may also lead to an increase in anxiety. Venlafaxine and duloxetine have also been reported to lead to increased blood

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pressure. Mirtazapine and mianserine often lead to weight gain and drowsiness, two effects that can lead to resistance, particularly on the part of female patients at the end of the period of treatment who are already exposed to weight gain owing to other mechanisms. There are no restrictions relating to prescriptions for patients with suicidal thoughts. According to the review conducted by Mo¨ller [50], the risk that such patients will actually take their own lives under the influence of antidepressants appears to be small and decreases from the age of 30 years onwards. If possible, patients who express suicidal thoughts should rapidly be sent for psychological or psychiatric assessment. However, if these thoughts are associated with depression, this referral should not cause any delay to treatment. A drug with only a low stimulant effect (a pure serotoninergic drug such as citalopram or paroxetine, but no noradrenergic products) should be preferred and should only be prescribed for a short initial period (1 week), after which the patient should be reassessed. If there is a risk of suicide, the introduction of the antidepressant treatment is an emergency, but not such as the organisation of the care that is to be received. While awaiting the results of psychiatric assessment, it is necessary to organise enhanced monitoring of the patient and inform his or her family of the suicidal risk, insofar as professional ethics permit this. Ensuring that the patient is accompanied as much as possible is an important factor in helping to prevent the occurrence of suicide. In all cases, it may be of value to try to limit the patient’s impulsivity by prescribing a sedative and anxiolytic neuroleptic such as cyamemazine (e.g. 25–50 mg/day). Antidepressants present no carcinogenic risk, at least in the case of SSRIs and tricyclics [51]. Nevertheless, vigilance is recommended in the case of the prolonged administration (more than 10 years) of serotonin–norepinephrine reuptake inhibitors (SNRIs), since for these recent products it has not yet been possible to study the associated long-term risks. The risk of serotonin syndrome is also frequently cited. This takes the form of excessive serotonergic stimulation which causes motor excitation, hyperreflexia, trembling, myoclonia and dysfunctioning of the autonomous central nervous system and, in extreme cases, epilepsy, comas or death. These effects are not due to any idiopathic effect but are caused by the interaction of drugs sharing similar mechanisms or by overdoses [52]. It is extremely difficult to state their frequency since minor forms are probably not recognised and still less often reported [52]. Although a treatment can start to have an effect as of the first few days following prescription, it cannot be viewed as ineffective until 3–4 weeks of administration at an effective dosage level (6 weeks in the case of elderly subjects). The effective dosage can sometimes vary considerably (by a factor of 1–3 or even 1–4), which means that in the case of lack of efficacy it is necessary, providing that the patient tolerates the drug without difficulty, to progressively increase the dosage before moving on to a new drug. If a drug appears to be ineffective, it is also necessary to verify correct adherence

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(and therefore also tolerance to the correct dosage) on the part of the patient. The minimum period of treatment is 6 months in order to avoid any premature relapse. Treatment must not be interrupted suddenly given the risks associated with withdrawal which, with paroxetine, may appear in less than 48 hours. If oral administration is impossible, it is generally possible to replace the prescribed drug with injectable citalopram, the only SNRI available in this form. If administration has to be performed via a tube, then drugs available in soluble form should be preferred (citalopram, mirtazapine, fluoxetine and paroxetine). Table 2 lists the main limitations to prescriptions and contraindications. This should be updated by the clinician in the light of the data available at the time of prescription. There are also risks of interactions with other drugs or of overdoses. Serotonin reuptake inhibitors are Cyt P450 substrates and may accumulate in individuals with slow metabolism or if Cyt P450 is inhibited. The SNRIs are also CytP450 inhibitors whose effect varies from drug to drug (in contact with different isoenzymes). There is therefore a risk of interaction. This is due as much to the accumulation of the substrate as to its ineffectiveness when in the form of an inactive prodrug. The important thing is to be aware of the possibility of interactions and to be vigilant [53]. Several internet sites provide regularly updated information that can be consulted if required. Although the prescription of psychostimulant drugs (primarily methylphenidate or modafinil) may be considered in the case of depressed patients (but in most countries remains outside the scope of marketing authorisation), this should be done only following a specialist assessment; in any case, these products are nowadays subject to an initial psychiatric prescription. Their stimulant effect on vigilance and attention may be of particular value in cases of asthenia associated with the prescription of opiates to overcome pain. In some studies, these drugs have exhibited a rapid antidepressant effect which can be of value, in particular when the end of life is near at hand and the period of action required by antidepressants is therefore unacceptable or in order to obtain an immediate effect during this end-of-life period. However, highquality studies, in particular involving adequate sample sizes, are still required in this area. Such psychostimulants should be prescribed only to patients for whom the experience of fatigue and the functional constraints that this imposes are perceived as an additional source of stress or an intolerable limitation to their quality of life. Their prescription should never be influenced by a desire for increased performance, in particular when made by friends and family distressed by the patient’s waning enthusiasm and drive and who would be reassured to see him or her recover the roles which he is no longer able to assume.

9. Is it necessary to prescribe a benzodiazepine? These drugs should not be prescribed systematically. In practical terms, it is justifiable to prescribe a benzodiazepine or anxiolytic:

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Table 2 – Main limitations to antidepressant prescriptions and contraindications. Moderate renal or hepatic insufficiency Severe hepatic insufficiency Conduction disorders Extension of QT, or co-prescription with drugs associated with this risk Cardiac disorders in general Hyponatremia Convulsions or risk of convulsions (cerebral metastases) without anticonvulsive treatment Arterial hypertension Prostatic adenoma

Administration of tamoxifen

SSRI, generally not contraindicated; use the minimum effective dose and start off with half this dose Use tianeptine or minalcipran Avoid tricyclics Avoid SNRIs Prefer mianserine Risk of aggravation in response to SNRIs: monitor Only tianeptine does not reduce the threshold of epileptogenesis

Avoid venlafaxine Tricyclics are contraindicated. Caution is necessary with minalcipran and mirtazapine, SNRIs authorised but possibility of urination difficulties Paroxetine and fluoxetine are contraindicated.

SSRI : selective serotonin reuptake inhibitors.

•

•

In the presence of a high level of anxiety, in particular in combination with somatic symptoms which might result in the poor tolerance of antidepressants (attribution to the drug of functional symptoms caused or exacerbated by anxiety). If the patient is already being treated with a benzodiazepine – this may subsequently be interrupted; however, stopping it straight away may aggravate the clinical picture because of drug withdrawal (which, once again, risks being incorrectly attributed to poor tolerance of the antidepressant).

In depressed, impulsive patients it is often preferable to treat anxiety with low doses of a sedative neuroleptic (e.g. cyamemazine) rather than with a benzodiazepine.

10. What are the roles of the different actors in diagnosing and caring for depression in the field of cancerology? Various organisational schemas for care administration in response to depressive disorders have been evaluated as a function of the actors responsible for screening, diagnosing or prescribing treatment [54]. It is not essential for the initial prescription to be made by a psychiatrist, in particular given the facts that there are not enough psychiatrists to provide care to all depressed patients, and that some of these patients are reluctant to consult a mental health specialist. Systematic screening followed by the diagnosis and the prescription of treatment by the oncological team itself appears to be the most efficient way of providing effective treatment [42] if it includes the arrangement of – at the very least – support services (coordinating nurse, possibly communicating by telephone etc.) or other psychotherapeutic services. A psychiatrist may assist in the task of prescribing in the most complex cases. This approach has been validated in North America and

seems to be suitable for use in the European context. It allows issue of an initial prescription without waiting for the psychiatrist, and emphasises the value, in addition to the prescribed antidepressant [1], of providing to the patient individual support by a psychologist or a nonpsychologist. It is advisable to obtain a psychiatric opinion from the outset in the case of patients with schizophrenia, a unipolar or bipolar mood disorder (manic-depressive disorder), a severe personality disorder or suicidal thoughts. A psychiatric opinion should also be sought as a second line of treatment in the event of resistance to treatment even after an increase in dose, or in the case of any doubt concerning the diagnosis. Even in the absence of a psychiatric opinion, the question of hospitalising the patient should be discussed if there is a risk of suicide or, in the case of refusal of treatment, agitation, extreme anxiety or delirium. It might also be considered in the case of extremely isolated patients. All authors have emphasised the value of offering psychological support to patients, either in the form of psychosocial support or in the form of psychotherapy. In major depressive disorders, combining the administration of an antidepressant with the provision of psychotherapeutic care improves the effectiveness of treatment. In a meta-analysis of depression in a non-cancerological environment (n = 1843), patients treated with a combination of psychotherapy (of all types) and antidepressants exhibited a considerably higher level of improvement than patients treated with drugs only (OR 1.86, 95%CI 1.38–2.52). Furthermore, the beneficial effect of this combination increased in the case of treatments lasting for 3 months or longer (OR 2.21, 95%CI, 1.22–4.03) [55]. In this context, initial prescription by a psychiatrist would be ideal in order to improve the diagnosis and ensure, from the outset, that the prescription forms part of a coordinated therapeutic approach, possibly accompanied by a psychotherapeutic element [56]. However, this solution is only rarely available.

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Fig. 1 – Summary of the main stages during diagnosis and the prescription of an antidepressant.

Various types of psychotherapy have been proposed, sometimes in combination: • • • • • •

Psychoeducation. Relaxation training. Problem-solving therapies. Cognitive behavioural therapies. Interpersonal therapies. Supportive expressive therapy.

The degree to which these therapies have been validated is sometimes limited and, in both psycho-oncology and psychiatry, the question of the evaluation of psychotherapies and psychosocial interventions continues to be a complex subject. The differing natures of the cancer patients, the approaches

and therapeutic goals, the training and experience of the therapists, and the multiplicity of assessment scales, as well as the different periods studied during the health care circuit, all further complicate such analyses and relativise the results [57–59]. In this field, the very idea of randomised trials can be called into question [60] since they do not make it possible to appraise the subtle effects and individual benefits brought about by psychotherapy. Beyond the above reservations, it is accepted that psychotherapies have a beneficial impact on anxiety, depression, psychological distress and quality of life [61,62]. Although it also seems to be the most depressed patients who gain the greatest benefits [63,64], this is at the same time the population for which the lowest level of evidence is available in the field of cancerology (only three well-conducted studies

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involving CBT and, in the case of metastatic patients, supportive–expressive therapies) [65]. It is important to identify the psychotherapeutic technique that is best suited for each patient as a function of their personality, their expressive capacities, their psychosocial situation, their concern for others and the time at which oncological care is administered. Thus, patients at the start of treatment might more readily accept a cognitive or psycho-educational approach, whereas those suffering from a recurrence of the disease or confronted with a serious development in its course might request a more existential form of psychotherapeutic support. Psychotherapies inspired by psychoanalytical and/or psychocorporal techniques could ideally be offered to all patients who request them provided that their psychotherapists are able, during preliminary interviews, to assess their ability to commit themselves to such activities and benefit from them. Fig. 1 summarises the main stages during diagnosis and the prescription of an antidepressant.

R E F E R E N C E S

11.

Conclusion

Depression remains highly prevalent in cancer patients, and appears to have a great impact on their quality of life as well as on certain cancer outcomes, even if probably by the means of its impact on compliance, physical activity, social support etc. This broad impact justifies carrying out systematic screening that can be performed by standardised tools but also by one or two simple questions. To be useful, this screening must be followed by an adequate clinical diagnosis that relies on a precise identification of emotional and cognitive symptoms of depression. Considering the prevalence of depressed patients, the oncological teams are expected to do the depression diagnosis and make the first antidepressants prescription by themselves. To be efficient, depression care must be part of a comprehensive care plan, including treatment of somatic symptoms, and an adequate response to information needs and unmet needs. When possible, and if accepted by the patient, the help of a psychologist is highly appreciated. In all cases, patients should benefit from an accompaniment that can be ensured by a nurse or a social worker. More research is still needed on factors that may cause varying rates of depression and that predict which patients are mostly at risk. An adequate collaborative care process ranging from depression screening to effective treatment has to be implemented and assessed. Longitudinal studies are still needed to understand the evolution of depressive symptoms. Randomised controlled trials should also help to differentiate between the effectiveness of types of psychosocial interventions. Newer antidepressants and stimulants also should be studied in this population.

Conflict of interest None declared.

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[42] Ell K et al. Randomized controlled trial of collaborative care management of depression among low-income patients with cancer. J Clin Oncol 2008;26:4488–96. [43] Rayner L, et al. Antidepressants for depression in physically ill people. Cochrane review; 2010: issue 4. [44] Musselman DL, Lawson DH, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001;344:961–6. [45] Cipriani A et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009;373:746–58. [46] Holland JC, Romano SJ, et al. A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. Psychooncology 1998;7:291–300. [47] Pezzella G, Moslinger-Gehmayr R, et al. Treatment of depression in patients with breast cancer: a comparison between paroxetine and amitriptyline. Breast Cancer Res Treat 2001;70:1–10. [48] Musselman DL, Somerset WI, et al. A double-blind, multicenter, parallel-group study of paroxetine, desipramine, or placebo in breast cancer patients (stages I, II, III, and IV) with major depression. J Clin Psychiatry 2006;67:288–96. [49] Rodin G, Lloyd N, et al. The treatment of depression in cancer patients: a systematic review. Support Care Cancer 2007;15:123–36. [50] Mo¨ller HJ. Do SSRIs or antidepressant in general increase suicidality? Eur Arch Psychiatry Clin Neurosci 2008;258(Suppl 3):3–23. [51] Coogan P. Review of 2000 the epidemiological literature on antidepressant use and breast cancer risk. Expert Rev Neurother 2006;6:1363–74. [52] Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112–20. [53] Yap KY-L, Tay WL, Chui W, Chan A. Clinically relevant drug interactions between anticancer drugs and psychotropic agents. Eur J Cancer Care 2011;20:6–32. [54] Gilbody S, Bower P, et al. Collaborative care for depression: a cumulative meta-analysis and review of longer-term outcomes. Arch Intern Med 2006;166:2314–21. [55] Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza C. Combined pharmacotherapy and psychological treatment for depression: a systematic review. Arch Gen Psychiatry 2004;61:714–9. [56] Pasquini M, Biondi M. Depression in cancer patients: a critical review. Clin Pract Epidemiol Ment Health 2007;3:2. [57] Stanton AL. How and for whom? Asking questions about the utility of psychosocial interventions for individuals diagnosed with cancer. J Clin Oncol 2005;23:4818–20. [58] Kissane DW, Grabsch B, et al. Supportive-expressive group therapy for women with metastatic breast cancer: survival and psychosocial outcome from a randomized controlled trial. Psychooncology 2007;16:277–86. [59] Boesen EH, Johansen C. Impact of psychotherapy on cancer survival: time to move on? Curr Opin Oncol 2008;20: 372–7. [60] Cunningham AJ, Edmonds CV, et al. A randomized controlled trial of the effects of group psychological therapy on survival in women with metastatic breast cancer. Psychooncology 1998;7:508–17. [61] Sheard T, Maguire P. The effect of psychological interventions on anxiety and depression in cancer patients: results of two meta-analyses. Br J Cancer 1999;80:1770–80. [62] Osborn RL, Demoncada AC, Feuerstein M. Psychosocial interventions for depression, anxiety, and quality of life in cancer survivors: meta-analyses. Int J Psychiatry Med 2006;36:13–34. [63] Blake-Mortimer J, Gore-Felton C, et al. Improving the quality and quantity of life among patients with cancer: a review of

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Anxiety and sleep disorders in cancer patients Maria Die Trill

*

Hospital Universitario Gregorio Maran˜o´n, Psycho-Oncology Unit, Madrid, Spain

1.

Introduction

Even though most cancer patients do not meet diagnostic criteria for any specific mental disorder [1], many experience symptoms such as anxiety and sleep disturbances that may interfere with their overall adjustment to their disease. Anxiety is a common reaction to a cancer diagnosis and a normal response to perceived threats like loss of body functions, alterations in appearance, family disruption, death, etc. Anxiety may persist throughout the disease process, affecting the patient’s quality of life significantly, and often coexists with depression in cancer patients. Anxiety tends to appear or worsen at critical points during the course of the illness (diagnosis, beginning and end of treatment, recurrence, survival and terminal stage). Sleep disorders are frequently associated with the psychological impact of cancer as well as with the physical illness itself, pain, hospitalisation and specific medical treatments. Altered sleep adversely affects emotional wellbeing and daytime performance, and may be an early sign of delirium in the oncology setting. In the general population, persistent insomnia has been associated with a higher risk of developing clinical anxiety or depression [2]. To effectively adjust patient needs to optimal treatment interventions, health-care professionals must be able to distinguish normal adjustment to cancer from altered reactions to the disease. This paper will focus on anxiety and sleep disorders in the oncology setting and will describe their clinical presentation, assessment, aetiology and treatment.

2.

Anxiety in the cancer setting

2.1.

Description and prevalence

Anxiety is defined as the apprehensive anticipation of future danger or misfortune accompanied by feelings of dysphoria or somatic symptoms of tension [3]. Classification systems used in psychiatry – such as the World Health Organization International Classification of Disorders [4] – require (a) a core of anxiety symptoms such as palpitation or tremor, manifest-

ing the presence of autonomic overactivity, and (b) anxiety to be abnormal, in order to fulfil a diagnosis of anxiety disorder [5]. While anxiety is a normal reaction to threats such as cancer, some patientU:/ES/DTD520/EJCSUP/204s exhibit an overwhelmingly anxious response that impairs their day-to-day functioning. Frequently, anxiety increases as the disease progresses or as treatment becomes more aggressive [6], as well as at transition points that represent threatening events throughout the course of the disease. Patients receiving a cancer diagnosis, learning about a recurrence, or hearing that treatment has been ineffective usually experience initial shock or disbelief followed by emotional turmoil, anxiety and depressive symptoms [7]. Inability to concentrate, diminished sleep, loss of appetite, irritability and intrusive thoughts about the future are also frequent at these times. However, these symptoms tend to decline gradually and resolve within the first 7–10 days after confirmation of cancer diagnosis [8]. Anxiety may affect a person’s behaviour regarding his/her health, contributing to a delay in or neglect of measures that might prevent or treat cancer adequately. Anxiety can lead to an overestimation of negative prognosis. For example, women with high levels of anxiety who learn that they have a genetically higher level of risk of breast cancer than they had previously believed might perform breast self-examinations less frequently [9]. A longitudinal study of women with breast cancer found that anxiety was the factor that was most consistently and strongly associated with an inaccurate perception of and an overestimation of future breast-cancer-related risk [10]. Anxiety may also delay or interfere with the seeking of medical care once symptoms have developed, adversely influencing – in this case – prognosis. As mentioned already, in most cases the anxious reactions are time-limited and may motivate patients and families to take steps to reduce the reactions, such as seeking medical advice, which may assist in adjusting to the illness. Anxiety may also be part of a normal adaptation to cancer. Normal or successful adjustment is indicated in patients who are able to minimise disruptions to life roles, regulate emotional distress and remain actively involved in aspects of life that con-

* Tel.: +34 677 450 889. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright  2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.009

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tinue to hold meaning and importance for them [11]. Clinical practice shows that anxiety may also decrease as patients accept and come to terms with their medical situation, despite disease progression. In the United States (US), 1-year prevalence for all anxiety disorders among adults in the general population exceeds 16% [12], and in the United Kingdom (UK) reported prevalence is between 3% and 16% [13]. Anxiety occurs to varying degrees in patients with cancer. Our limited understanding of anxiety in cancer care is illustrated by the wide range of prevalence estimates of abnormal anxiety in cancer patient populations [5]. Estimated current prevalence of anxiety disorders in oncology is within a range 15–28% [14], with variations being due to differences in research methodology. In large studies using standardised psychiatric interviews and applying research diagnostic criteria, estimates of abnormal anxiety in cancer populations ranged from 10% to 30% [4]. Some researchers have found that up to 44% of patients with cancer reported some anxiety, and 23% reported significant levels of anxiety [5,15]. Variation in reported prevalence is due largely to limitations in research methodology: differing study populations (single versus mixed cancer diagnosis, differing tumour sites, early- versus late-stage disease, outpatient versus inpatient; etc.), varying diagnostic criteria and assessment instruments and studies failing to separate anxiety from depression, etc. Some researchers suggest that anxiety disorders are also prevalent in medically ill patients in general [16]. However, rates of anxiety disorders among primary care outpatients have ranged from 7% to 15% [17], and among general medical inpatients rates of 20% have been reported [18]. In both cases, reported rates seem to be lower than those reported in cancer patients. However, populations studied have varied widely in disease severity and prognosis [16]. In cancer patients symptoms of anxiety often coexist with depression and mixed states, and are perhaps more common than anxiety alone [1,19].

2.2.

Clinical presentation and pathological anxiety

In order to understand anxiety we need to differentiate between anxiety as a state and anxiety as a relatively stable personality characteristic or trait (state versus trait anxiety). Patients with high levels of trait anxiety will carry their predisposition throughout the disease course, and thus it is important to identify it in an early phase. Symptoms are similar in most patients, regardless of whether they represent acute responses to cancer or its treatment, or are part of a pre-existing anxiety disorder, exacerbated by the diagnosis of cancer [16]. Acute anxiety symptoms include: • • • • • •

uneasiness, unpleasant feeling of arousal, restlessness; irritability; inability to relax; tendency to startle; difficulty falling asleep (leads to fatigue and low tolerance to frustration); recurring, intrusive thoughts and images of cancer; occasionally, sense of impending doom;

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• • •

• •

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distractibility; helplessness and a sense of loss of control over one’s own feelings; symptoms of autonomic arousal: rapid or forceful heartbeat, sweating, unpleasant tightness in stomach, shortness of breath, dizziness; vegetative disturbances: loss of appetite, decreased sexual interest; parasympathetically-mediated symptoms: abdominal distress, nausea, diarrhoea.

Pathological anxiety can be identified because it tends to be out of proportion to the level of threat; it persists or deteriorates when no intervention is administered, the intensity of symptoms is unacceptable regardless of the intensity of the threat (these include panic attacks, severe physical symptoms, abnormal beliefs such as thoughts of sudden death), and the patients experience a disruption of their usual or desirable functioning [3,4]. However, such criteria are difficult to apply to cancer patients given that cancer is always associated with some form of threat: the threat of loss, death, body functions, roles, body image, etc. In addition, while the duration of symptoms is important in identifying abnormal anxiety, the natural history of anxiety in oncology is uncertain. Disruption of functioning is also common in cancer patients and is frequently associated with anxiety (i.e. intrusive and unpleasant thoughts regarding recurrence, disability or death can disrupt the ability to concentrate, decision-making, sleep patterns, etc.) [4]. Massie and Shakin [20] have categorised anxiety in cancer patients into three groups: reactive anxiety, pre-existing anxiety disorders and anxiety related to medical illness. Reactive anxiety: Adjustment disorders are emotional reactions to an identifiable stressor, in this case the disease, with a degree of psychopathology that is less severe than diagnosable mental disorders such as generalised anxiety. The patient experiences significant distress that is in excess of what would be expected from exposure to the stressor and a significant impairment in functioning.

CASE: Ms E, a 56-year-old woman recently diagnosed with colon cancer, was referred to the Psycho-Oncology Unit because of increased anxiety that interfered with her ability to decide whether to receive treatment with chemotherapy (CT) or not. Ms E had cared for her mother, who had died of ovarian cancer 2 years earlier after suffering severe treatment toxicity. Psychotherapy focused, among other things, on improving coping skills, deconstructing myths about cancer and its treatment, strengthening supports and introducing the patient to others that had successfully undergone cancer treatment, as well as practicing relaxation techniques in the oncology clinic where treatments were administered. Once her anxiety was significantly reduced, the patient decided to undergo treatment, which ended successfully.

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Of hospitalised and ambulatory cancer patients, 32% were found to meet diagnostic criteria for an adjustment disorder [1]. In patients with advanced cancer, prevalence ranges from 14% to 35% [21], and in terminally ill patients rates range from 11% to 16%. Variability in prevalence rates is due to different factors such as differences in stage of disease, type of cancer or diagnostic procedures used for anxiety. The difference between an adjustment disorder and a normal reaction to cancer is based primarily on the duration and intensity of symptoms, as well as on the degree of functional impairment. Pre-existing anxiety disorders: Panic disorders, phobias, generalised anxiety disorders and post-traumatic stress disorder are distinguished from other anxiety disorders as being long-lasting, often preceding the diagnosis of cancer. They are characterised by the extreme fear of losing control and of being overwhelmed by various circumstances: Panic attacks are sudden, extreme anxiety reactions accompanied by sympathetic nervous system arousal and an overwhelming urge to escape. Intense anxiety is usually accompanied by severe somatic symptoms such as shortness of breath, dizziness, palpitations, trembling, diaphoresis, nausea, tingling sensations and fears of going crazy or having a heart attack. Panic attacks may be re-experienced when the patient is exposed to medical procedures, treatment toxicity, etc.

CASE: Ms. A, a 35-year-old woman diagnosed with breast cancer requested psycho-oncological consultation for recurring panic attacks that developed shortly after ending cancer treatment. Ms A described herself as a very controlling, perfectionist, anxious and selfdemanding woman for whom the disease was not a logical consequence of her previous behaviour, which had focused on healthy eating habits, reduced alcoholic intake, no smoking and almost daily exercise. She was experiencing between one and three panic attacks per week. Psychotherapy focused on helping the patient regain a sense of control over her life, focusing on the here-and-now while accepting her cancer risk, and developing more efficient ways of handling her anxiety, together with cognitive-behavioural techniques (i.e. training in relaxation, deep breathing techniques, etc.). Pharmacological treatment with benzodiazepines contributed to making the panic attacks disappear.

Phobias are persistent fears, intense anxiety or avoidance of a circumscribed object or situation. Phobias are experienced by cancer patients in a number of ways, the most common of which are fears of witnessing blood or tissue injury (also known as needle phobia) or claustrophobia (fear of closed places). Phobias may interfere with the administration of cancer treatment with patients refusing medical treatment or necessary tests [22], and may lead to anticipatory anxiety [16].

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Mr E was a 28-year-old male with testicular cancer who had a needle phobia. Each time the patient had to undergo blood tests or receive IV chemotherapy treatment, his anxiety escalated to the point where, on one occasion, his treatment had to be postponed to the following day. Training in relaxation as well as in deep breathing techniques alternated with techniques to help him regain control over the situation. For example, it was himself who counted to three before the nurse administered the procedure, which increased his perception of control over the situation. Mr E was trained to do breathing exercises with the use of a party blower. In addition, he learned to identify a positive thought for each negative thought he had, prior to the procedure. For example, ‘This is really going to hurt’ was accompanied by ‘Feeling the needle is not going to be very pleasant, but it will help cure my disease’. Mr E was able to undergo treatment with reduced levels of anxiety.

Generalised anxiety disorder is characterised by ongoing, unrealistic and excessive anxiety and worry that the patient finds difficult to control. The worry is pervasive and does not respond to either reassurance or contrary evidence. Symptoms do not have either the sudden onset or intensity of panic attacks and include restlessness, muscle tension, being easily fatigued, irritability, difficulty concentrating and sleep disturbance. Cancer patients with generalised anxiety disorder may, for example, worry or fear that no one will care for them, even though they have adequate social support, or they tend to anticipate medical complications. Post-traumatic stress disorder (PTSD) develops when a person is exposed to a mentally stressful event that involved actual death or the threat of death, serious injury or a threat to oneself or others, and responds with intense fear, helplessness or anxiety. The person with PTSD re-experiences the traumatic event persistently in the way of recurrent and intrusive distressing images or thoughts, dreams of the event, avoids situations associated with the trauma, and experiences persistent symptoms of increased arousal that were not present prior to the trauma. To be diagnosed with PTSD, these symptoms must last for at least 1 month and cause significant problems in the patient’s personal relationships, employment or other important areas of daily life [3]. For the person who has experienced a diagnosis of cancer, the specific trauma that triggers PTSD is unclear. It may be the actual diagnosis of a life-threatening illness, certain aspects of the treatment process, test results, information given about recurrence or some other aspect of the cancer experience. Because the cancer experience involves so many upsetting events, it is much more difficult to single out one event as a cause of stress than it is for other traumas, such as a natural disaster or rape. PTSD has been studied in longterm non-Hodgkin’s lymphoma survivors who had participated in an earlier survey and were at least 7 years post-diagnosis [23]. Although half of the respondents reported no PTSD symptoms and 12% reported a resolution of symptoms, more than one third (37%) reported persistence or worsening

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of symptoms over 5 years. Those who had a low income, more advanced illness at diagnosis (stage P2), aggressive lymphoma, having received chemotherapy and greater impact of cancer at the initial survey had more PTSD symptoms at follow-up. Cancer survivors with PTSD may relive the cancer experience in nightmares or flashbacks and by continuously thinking about it; they may avoid places, events and people associated with the cancer experience, and may tend to be continuously overexcited, fearful, irritable and unable to sleep.

Mr K was a war veteran who underwent a bone marrow transplantation for leukaemia. During hospital isolation, Mr K started re-experiencing the time when he was imprisoned and placed in a cell, isolated for a prolonged period of time, during the war. In the hospital he had recurrent and intrusive images and thoughts about the war episode, frightening dreams of the event, and flashback episodes that gave him a sense of reliving the traumatic event. Other symptoms he exhibited included hypervigilance, insomnia, difficulty concentrating and avoidance of conversations related to the war episode when he was imprisoned. Benzodiazepines were administered. In addition, he was trained in different video games that provided him with cognitive distraction. In the evenings, when other patients were asleep and visitors had left the hospital, Mr K had to be walked in a wheelchair, the appropriate protective measures having been taken, up and down the hallways of the hospital floor to alleviate his sense of being ‘locked up’. Obsessive-compulsive disorder is characterised by: (a) recurrent, persistent thoughts, ideas or images (obsessions) that cause marked anxiety or distress, and are experienced as intrusive and inappropriate, and (b) repetitive, purposeful and intentional behaviours (compulsions) that the patient performs in response to an obsession in an attempt to reduce his/her distress. In order to diagnose an obsessive-compulsive disorder, the obsessions or compulsions should cause marked distress, should be time-consuming (take more than an hour a day) and interfere with the person’s normal routine or functioning [3].

Ms T was a 34-year-old woman who had been treated for skin melanoma. Her skin was extremely white and full of freckles all over her face, body and extremities. Ms T was referred to the Psycho-Oncology Unit by her dermatologist, whom she visited frequently and unnecessarily. The patient would spend more than 2 h daily observing her freckles and trying to identify changes in any one of them. She involved her husband in helping her with this task, as she couldn’t view her back. This habit became increasingly incapacitating for the patient, and a source of irritation for her husband. The patient was treated with antidepressant medication and initiated psychotherapy sessions that helped reduce her distress as well as confront her underlying fear of death and other internal conflicts she had.

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Anxiety related to medical illness uncontrolled pain, metabolic causes, medication side effects, withdrawal states and hormone-producing tumours may result in increased anxiety levels in the cancer patient. Patients with severe pain are usually anxious, and anxiety in turn can potentiate the pain sensation. Consequently, it is important to treat anxiety in order to adequately manage pain [24]. Anxiety may be the first sign of a change in metabolic state. Sepsis accompanied by chills and fever is often associated with anxiety. Delirium may cause symptoms of anxiety, restlessness and increased agitation. Certain drugs used in cancer, such as corticosteroids, are frequently a cause of anxiety symptoms such as restlessness and agitation. Akathisia is a side effect of several neuroleptic drugs that are frequently used for control of emesis. Withdrawal states from alcohol, narcotic analgesics and sedative hypnotics are often overlooked as causes of anxiety [20]. This is an especially important issue in head and neck cancer patients who often have histories of heavy alcohol and tobacco consumption that place them at increased risk for withdrawal states. Hormone-secreting tumours such as thyroid and parathyroid tumours may be associated with anxiety symptoms.

2.3. Variables associated with anxiety in the cancer setting Cancer is usually an emotionally stressful event in the lives of patients. In addition to physical discomfort, patients typically face dysfunction, alterations in appearance, changes in family and social roles, disruption of work activities and other complex situations. Various factors have been associated with anxiety in cancer patients. Among them are: •

•

history of anxiety disorders: premorbid anxious tendencies such as elevated trait anxiety and obsessive personality traits [25,26]; helplessness, fatalism and anxious preoccupation have also been correlated with anxiety in breast cancer patients [27]; psychological variables such as anxiety at the time of diagnosis [28] and history of trauma [29].

Previously discussed factors have been associated with anxiety in cancer patients and include history of anxiety disorders [25–27] and psychological variables such as anxiety at the time of diagnosis [28] and history of trauma [29]. In addition, medical/physical variables such as functional limitations, pain (described earlier) and advancing disease [6] have been associated with increased levels of anxiety in cancer patients. Cancer treatments, specifically the type of treatment administered and tumour response, have also been associated with elevated anxiety [30]. Anxiety is experienced by patients with anticipatory nausea and vomiting (ANV), a phenomenon that results from a classical conditioning process by which stimuli repeatedly associated with chemotherapy end up producing nausea and emesis prior to treatment administration. Anxious patients seem to develop anticipatory nausea and vomiting more frequently than non-anxious patients [31]. In these cases, patients may feel nauseous or vomit the week/day before treatment, as they approach the clinic, or even just thinking about chemotherapy.

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2.4.

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Screening and assessment

Optimal management of anxiety disorders requires a comprehensive assessment and an accurate diagnosis. The distinction between normal fears and more severe fears that reach criteria for an anxiety disorder is not always clear in the cancer setting. According to Nicholas [32], patients with normal worry compared to those with more serious symptoms of anxiety disorders have only some difficulty concentrating, are able to ‘turn off thoughts’ most of the time, have occasional trouble falling asleep, and crying spells that seem to provide relief, and have few, if any, physical symptoms such as dry mouth, restlessness or racing heart. Worry comes and goes in this group of patients. On the other hand, patients with severe anxiety symptoms are unable to concentrate and to ‘turn off thoughts’ most of the time, have sleep problems most nights as well as crying spells that interfere with daily activities, experience constant worries and have few ways of reducing anxiety. It is important to understand the extent to which anxiety interferes with daily living and quality of life. Psychometric instruments may be used to complement the clinical interview when assessing anxiety. The scales most frequently used with cancer patients include: •

•

•

•

•

hospital anxiety and depression scale (HADS) [33], which is a 14-item scale measuring symptoms of clinical depression and anxiety; brief symptom inventory (BSI) [34], which is an 18-item scale measuring somatisation, depression, anxiety and general distress; profile of mood states (POMS) [35], which is a 65-item scale measuring six mood states: anxiety, fatigue, confusion, depression, anger, vigour; state-trait anxiety inventory (STAI) [36], which is a 40-item measure that indicates the intensity of feelings of anxiety; STAI differentiates between state anxiety (a temporary condition experienced in specific situations) and trait anxiety (a general tendency to perceive situations as threatening); distress thermometer and problem list, which consists of a 0–10 scale to measure distress that is accompanied by a problem list in which patients are asked to note the nature and source of their distress (physical, social, psychological or spiritual) [37].

Self-report screening instruments must be scored, evaluated and discussed with each patient, and are useful in providing the oncology team with notions of how anxious the patient is.

2.5.

Treatment of anxiety disorders

Psychosocial adjustment to cancer is an ongoing process in which the patient tries to manage emotional distress, solve specific cancer-related problems, and gain control over cancer-related events [38]. The purpose of treatment for anxiety in cancer patients is to facilitate successful adjustment to the disease: i.e. to help them minimise disruptions to life

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roles, regulate emotional distress and remain actively involved in aspects of life that continue to hold meaning and importance to them [11]. The average patient receiving psychosocial intervention for anxiety is less anxious than those not receiving the intervention. The overall positive benefit for psychosocial interventions seems to be greater with those who seem to need it most [39]. Treatment of anxiety should be multimodal, including a combination of pharmacotherapy and different psychotherapeutic interventions. Holland et al. [40], in a randomised study, compared relaxation with alprazolam in the treatment of anxiety and distress in cancer patients. Findings demonstrated both treatments to be equally effective for mild to moderate degrees of anxiety or distress. Alprazolam was more effective for greater levels of anxiety or distress, and had a more rapid onset of the beneficial effect. Medication is only considered when patients experience severe symptoms, when their anxiety does not respond to psychological intervention and/or when there are no psychosocial services available or the patient refuses to use them. Massie and Shakin [20] describe clear guidelines for the use of pharmacotherapy to treat anxiety in the oncology setting. The choice of benzodiazepine depends on the desired halflife, route of administration available, route of metabolism and the presence or absence of active metabolites. They suggest that drugs with shorter half-lives, multiple routes of administration and no active metabolites are preferable in the medically ill patient, as well as the use of low-dose antipsychotic medications in patients with severe anxiety when treatment with benzodiazepine has not been effective. Benzodiazepines are not indicated in patients with medical conditions such as delirium, because they may exacerbate confusion and disorientation. In any case, use of these agents should be closely monitored and anxiety symptoms re-evaluated, medication being tapered off as symptoms subside [41]. Psychological approaches in the treatment of anxiety include combinations of cognitive behavioural therapy (for example, calming self-talk), insight-oriented and supportive psychotherapy, crisis intervention, support and self-help groups, and relaxation-based interventions such as hypnosis, meditation, progressive relaxation, guided imagery and biofeedback. All have been proven to be effective in reducing anxiety in the cancer patient [42–46]. Different psycho-educational interventions are equally useful. They have aimed at replacing the sense of helplessness with a sense of control, and in the process, reducing psychological distress [16]. For example, a booklet with diseaserelated information was provided to patients with Hodgkin’s disease, and these patients experienced more reductions in their levels of anxiety than those who did not receive the booklet [47]. Psychoeducational interventions might be provided by the physician and/or nurse, through accurate medical information and support. Anxiety related to medical procedures may be reduced by adequate preparation by a staff member, such that the patient will most likely have more realistic expectations about the procedure. Regardless of the treatment modality employed to reduce anxiety in the cancer setting, organic causes of symptoms must be discarded prior to initiation of the intervention, and if detected, their correction should be a priority.

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2.6.

Sleep disorders

Sleep disorders are a common symptom of anxiety, one of the most prominent concerns of cancer patients [48], and one of the main reasons for consultation in oncology [49]. In the general population, people with insomnia report more medical problems than those without insomnia [50]. Altered sleep usually has a profound adverse effect on emotional, cognitive and physical functioning. Sleep consists of two phases: rapid eye movement (REM) sleep and non-REM (NREM) sleep [51]. REM sleep is the active or paradoxical phase of sleep in which the brain is active. It is also known as dream sleep. NREM sleep is the restful phase of sleep. Both phases alternate in a repeated pattern or cycle of NREM followed by REM, with each cycle lasting approximately 90 min. The sleep–wake cycle is dictated by an inherent biological clock or circadian rhythm. Disruptions in individual sleep patterns can disrupt the circadian rhythm and impair the sleep cycle [52].

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standing of the possible link between cancer-related fatigue and sleep disturbances suggests that interventions targeting sleep disorders and daytime sleepiness could provide promising potential treatments for cancer-related fatigue. Targeted treatment of either symptom may possibly affect the other, given the emerging data suggesting that sleep disturbance is common in patients with cancer and that it may be both a cause and an effect of fatigue [58]. The following risk factors have been described for sleep disorders in cancer patients [61]: •

•

• •

2.7.

Categories of sleep disorders •

The American Academy of Sleep Medicine [53] has defined five categories of sleep disorders: • • • • •

disorders of initiating and maintaining sleep: insomnias; sleep-related breathing disorders: sleep apnoea; disorders of excessive somnolence: hypersomnias; disorders of the sleep–wake cycle: circadian rhythm sleep disorders; dysfunctions associated with sleep, sleep stages, or partial arousals: parasomnias.

2.8.

Sleep disorders in cancer patients

Sleep disturbances occur in about 10–15% of the general population [54] and are often associated with situational stress, disease, ageing and drug treatment [55]. Between one third and one half of cancer patients experience sleep disorders [56]. These are usually associated with pain, hospitalisation, medication, recurring thoughts about the disease and cancer-related fears. Anxiety and depression have been found to be highly correlated with insomnia [56]. Alterations in the sleep–wake cycle can be early signs of delirium. However, insomnia is often under-recognised and undertreated, partly because it has been seen as a normal and transient reaction to cancer and cancer treatment, and partly because sleep disturbances are under-reported by patients [57]. Patients with cancer report insomnia, poor sleep quality and short sleep duration [58]. Sleep disturbances can persist in time, with a significant number of cancer survivors reporting them as one of the most pervasive problems they face. Reports over the past 20 years have begun to shed light on the putative relationship between cancer-related sleep disorders and cancer-related fatigue. While most of the studies in this area are correlative in nature, it is generally the case that sleep disturbance is: (a) positively correlated with fatigue, (b) more severe in fatigued than in non-fatigued patients and (c) a significant predictor of fatigue [58–60]. Current under-

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• • •

disease factors, including paraneoplastic syndromes with increased steroid production, and symptoms associated with tumour invasion (i.e. pain, fever, shortness of breath) [62]; treatment-related factors, including symptoms associated with surgery (i.e. pain, use of opioids and frequent monitoring) [62]; chemotherapy administration (i.e. exogenous corticosteroids); medications such as opioids, sedatives/hypnotics, steroids, some antidepressants and dietary supplements [63]; environmental factors (i.e. hospital routines and roommates, environmental noise) [64]; physical and/or psychological stressors [57]; anxiety and depression [56]; delirium.

In addition to considering the above risk factors, an adequate assessment of sleep disorders should evaluate the usual patterns of sleep, including usual bedtime, routine before retiring, length of time before onset of sleep and duration of sleep (waking episodes during the night, ability to resume sleep and usual time for awakening). Characteristics of disturbed sleep (changes following diagnosis, treatment and/or hospitalisation), perception of significant others as to quantity and quality of patients’ sleep, and family history of sleep disorders should be taken into account, together with emotional status, exercise and activity levels, diet and care-giver routines [53]. Some studies link sleep with natural killer cell activity [65] and conclude that sound sleep may be important for immune defence against tumour cells [66].

2.9.

Treatment of sleep disorders

Multiple psychological interventions – ranging from individual supportive psychotherapy to cognitive behavioural techniques (biofeedback, hypnosis, progressive muscle relaxation) – have proven to be effective in the control of anxiety and sleep disorders [67], and may be combined with pharmacological interventions. Several large randomised trials and meta-analysis have demonstrated the efficacy of cognitive behavioural therapy for insomnia in patients without cancer [68,69] as well as in the cancer population [70–72]. Components of cognitive behavioural therapy (CBT) include: •

cognitive restructuring, such as restructuring negative thoughts, beliefs and attitudes related to sleep, and preventing excessive monitoring or worrying about getting enough sleep [68];

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•

•

•

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behavioural strategies including stimulus control and sleep restriction in order to limit the time spent in bed during which the patient does not sleep [68]; relaxation techniques that can be combined with both cognitive and behavioural interventions are quite useful when accompanied by visual imagery; basic sleep hygiene education includes suggesting the following to the patient: sleeping and waking up at regular times, relaxing at least 90 min before going to bed; creating a dark, comfortable sleep environment with a cool temperature, avoiding watching television, using a laptop, or working in bed, getting ample daylight during non-sleep hours, avoiding day naps, avoiding stimulants such as caffeine, nicotine and cigarettes 2–3 h before bedtime, avoiding intake of liquids 2 h prior to sleeping, and getting regular exercise but no closer than 3 h before bedtime.

In one study, 30 cancer patients were assigned to either a three-session relaxation programme or no treatment. Patients receiving relaxation training reported reductions in sleep latency [70]. Espie et al. [72] found CBT to be associated with mean reductions in wakefulness of 55 min per night compared with no change for the care as usual group for persistent insomnia in patients with cancer. Results were sustained 6 months after treatment. Standardised relative effect sizes were large for complaints of difficulty initiating sleep, waking from sleep during the night and for sleep efficiency (percentage of time in bed spent sleeping). CBT was associated with moderate to large effect sizes for five of seven quality-of-life outcomes, including significant reduction in daytime fatigue. No significant interaction was found between any of these outcomes and baseline demographic, clinical or sleep characteristics. Savard et al. [71] studied 57 women with insomnia caused or worsened by breast cancer. Patients in the treatment group participated in CBT group sessions during eight weekly sessions of 90 min duration each, led by a psychologist. Sustained reductions in sleep latency and wakefulness were observed after CBT compared with controls. There was no increase in total sleep, but increases in sleep efficiency (proportion of time in bed spent asleep) averaged 15%. Long-term pharmacological treatment is not desirable, especially when fatigue is an issue [73,74]. Despite this, 25% of cancer patients have been reported to take sleeping pills on a regular basis [66], and approximately 25–50% of all prescriptions written for patients with cancer are for hypnotics [75]. In cases where CBT is not available, has not been successful, or when patients have comorbidities contributing to sleep disturbances (i.e. pain, hot flashes, depression, etc.), then pharmacological treatment will be necessary. Several types of medication are used to treat disturbed sleep [61]: non-benzodiazepine benzodiazepine receptor agonists, benzodiazepines, melatonin receptor agonists, antihistamines, antidepressants and antipsychotics that have sedative effects, and melatonin. Most of the approved sleep aids have not been studied in cancer populations; therefore the risk/ benefit profiles of these drugs are not delineated in this setting.

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3.

Conclusion

Patients with cancer report elevated levels of anxiety and sleep disturbances that may intensify throughout the disease course. Symptoms are frequently underestimated, despite the enormous adverse impact they have on patients’ quality of life. Adequate assessment of symptoms is imperative and should identify medical as well as non-medical variables influencing or causing anxiety or sleep disturbance, in order to obtain optimal symptom management. Psychotherapeutic techniques such as CBT have proved to be effective in controlling both anxiety and sleep disturbances. However, the most effective intervention for both anxiety and sleep disorders is that which combines psychotherapeutic techniques with pharmacological treatment, when necessary.

Conflict of interest statement None declared.

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[58] Roscoe JA, Kaufman ME, Matteson-Rusby SE, et al. Cancerrelated fatigue and sleep disorders. The Oncologist 2007;12:35–42. [59] Anderson KO, Getto CJ, Mendoza TR, et al. Fatigue and sleep disturbance in patients with cancer, patients with clinical depression, and community-dwelling adults. J Pain Symptom Manage 2003;25:307–18. [60] Broeckel JA, Jacobsen PB, Horton J, et al. Characteristics and correlates of fatigue after adjuvant chemotherapy for breast cancer. J Clin Oncol 1998;16:1689–96. [61] NCCN Practice Guidelines for the management of psychosocial distress. National Comprehensive Cancer Network. Oncology 1999;13:113–47. [62] Vena C, Parker K, Cunningham M, et al. Sleep–wake disturbances in people with cancer part I: an overview of sleep, sleep regulation and effects of disease and treatment. Oncol Nurs Forum 2004;31:735–46. [63] Barbera J, Shapiro C. Benefit–risk assessment of zaleplon in the treatment of insomnia. Drug Saf 2005;28:301–18. [64] Boonstra L, Harden K, Jarvis S, et al. Sleep disturbance in hospitalized recipients of stem cell transplantation. Clin J Oncol Nurs 2011;15:271–6. [65] Irwin M. Effects of sleep and sleep loss on immunity and cytokines. Brain Behav Immun 2002;16:503–12. [66] Davidson JR, MacLean AW, Brundage MD, et al. Sleep disturbance in cancer patients. Soc Sci Med 2002;55:313–22.

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Chemotherapy-related changes in cognitive functioning Sanne B. Schagen *, Jeffrey S. Wefel The Netherlands Cancer Institute, Division of Psychosocial Research and Epidemiology, Amsterdam, The Netherlands MD Anderson Cancer Center, Department of Neuro-Oncology, Houston, TX, USA

1.

Introduction

The potentially detrimental effects of cancer and related treatments on cognitive functioning are emerging as a key focus of cancer survivorship research. Many patients with central nervous system (CNS) or non-CNS tumours develop cognitive problems during the course of their disease that can result in diminished functional independence and can continue well into the survivorship period. In recent years, growing attention is being paid to the potential adverse effects of chemotherapy on brain and cognitive function. This central neurotoxicity may manifest as both acute and delayed complications. Virtually all categories of chemotherapeutic agent have been associated with adverse neurological effects, including both acute and chronic encephalopathy. More subtle cognitive dysfunction has also been demonstrated and frequently manifests as diminished memory, executive function, attention and information processing speed. In this article on chemotherapy and cognitive functioning we will summarise knowledge on the incidence of cognitive deficits, the neuropsychological pattern and structural brain changes associated with chemotherapy, risk factors identified for developing neurotoxicity and underlying mechanisms as well as current treatment options to prevent or diminish the adverse effects of chemotherapy on cognition. We will focus on chemotherapy-associated cognitive problems in breast cancer patients, as these symptoms have been particularly well studied in this patient group. In addition, studies on chemotherapy and cognition in adult CNS cancer patients will also be discussed. In this group of patients chemotherapy may be associated with stabilisation or improvement of cognitive function due to better disease control, but may at the same time go hand in hand with CNS toxicity as a consequence of chemotherapy.

2. Neuropsychological studies in breast cancer patients Over the last 10–15 years, increasing evidence has revealed the occurrence of acute and long-term cognitive problems for a subset of patients following chemotherapy applied in the treatment of non-CNS malignancies. In breast cancer patients alone, over 60 neuropsychological studies have been published that have investigated whether adjuvant chemotherapy is associated with cognitive impairment [1–3]. In the early years most of these studies had a cross-sectional design and provided us with a snapshot of the prevalence of cognitive impairment and the characteristics associated with this impairment at specific moments post-chemotherapy. In recent years, prospective neuropsychological studies on the incidence of cognitive problems arising from pre- to post-chemotherapy supported the previous observed relationship between chemotherapy exposure and cognitive problems by demonstrating cognitive decline post-treatment relative to pre-treatment cognitive performance. Those prospective studies with a pre-treatment assessment also indicated the importance of a baseline measure, as several studies observed lower than expected cognitive performance in breast cancer patients who are about to undergo chemotherapy in comparison to reference data of non-cancer subjects or cancer patients with lower disease stages who will not need chemotherapy. Up till now, no explanation has been found for these decreased cognitive scores at baseline. Surgery (under general anaesthesia), distress, fatigue or disease-associated immune responses cannot yet clarify this observation.

3. Frequency dysfunction

and

pattern

of

cognitive

The vast majority (70%) of the neuropsychological studies demonstrated cognitive impairment and/or cognitive decline

* Corresponding author. Address: Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. Tel.: +31 20 512 2328/2480. E-mail address: [email protected] (S.B. Schagen). 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.007

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in breast cancer patients who have been treated with cytotoxic agents compared to breast cancer patients without chemotherapy or compared to non-cancer controls, regardless of the design of the study. Patients show deficits on a wide range of standardised neuropsychological tests, but core impairments are related to learning new information and accelerated forgetting of information. Impairment in executive functions – such as planning and implementing strategies, flexible shifting and working memory – is also common, as are deficits in psychomotor speed (indicative of a frontal–subcortical profile). Despite the accumulation of knowledge on the cognitive side-effects of chemotherapy, the actual incidence of this impairment is still a subject of research. Estimates of affected patients vary from 17% to 78% across studies, because of differences between treatment regimens and between individual patients, but also owing to variations in study measures, assessment times and criteria applied to define cognitive impairment and deterioration. When the magnitude of the cognitive deficits as expressed in sizes of effects is studied, a large variation between studies is also observed.

4.

Course over time

The literature has shown that cognitive changes can arise during treatment and can persist up to several years after completion of treatment. Studies have largely followed patients up to 1–2 years post-treatment. Only a few studies have investigated the very late (i.e. P5 years post-treatment) effects of chemotherapy, but those that have show long-term cognitive problems in chemotherapy-exposed breast cancer survivors. A recent large study showed that breast cancer survivors who received CMF chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil) on average 20 years previously were more likely to have lower performance on memory, information processing speed and psychomotor speed compared with women without a history of cancer. The magnitude of the effects was comparable to approximately 6 years of age-related decline in cognitive function [4]. The influence of cancer and cancer treatment on the process of cognitive ageing is a topic that is increasingly receiving attention. There is concern that chemotherapy may induce accelerated ageing and that it can increase an individual’s susceptibility to late-emerging cognitive decline or dementia. The underlying development of cognitive impairment in ageing appears to begin at mid-life. Genetic signatures of brain ageing (i.e. from transcriptional profiling in post-mortem brains) can be identified in subjects as early as their 40s. Substantial evidence demonstrates that a wide variety of variables in early life are determinants of cognition in later life. Furthermore, both lifestyle and health-related risk factors in mid-life are associated with poor cognition decades later. It is plausible that damage to brain health in young to middle-aged women becomes even more clinically evident many years later when the brain is extra vulnerable. Therefore it is essential to investigate how chemotherapy in earlier life may influence cognition in later life. Different trajectories for chemotherapy-associated cognitive problems have been proposed in the literature. It could

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be that long-term cognitive problems result from lack of recovery from the acute effects of treatment. It could also be that the initial effect of treatment may produce a cascade of biological events that cause continued cognitive decline with ageing. Alternatively, chemotherapy may not be sufficient to cause enough redundancy loss to immediately affect cognitive function, but may produce a delayed effect as ageing continues, with the slope of change being influenced by a variety of factors [5]. Prospective studies with a very long-term follow-up or studies focusing on older cancer survivors are almost absent. A study on the effects of chemotherapy and cognition in patients P65 years of age showed that these subjects experienced more cognitive decline than unexposed counterparts. Incidence of dementia was not explored in this study, and even though these subjects were of older age, their mean time since treatment was still relatively short [6,7]. A few retrospective studies have been published examining the risk of dementia in breast cancer survivors up to 15 years after completion of cytotoxic treatment; these studies used data from the linked Surveillance, Epidemiology and End Results (SEER)–Medicare database. None of these studies showed any clear evidence for the existence of such a relationship, although several methodological issues limit the validity and interpretation of the studies [8– 11].

5.

Risk factors

Several factors have been identified that generally increase the risk of developing neurotoxicity associated with chemotherapy. These include: (1) exposure to higher doses due to planned use of high-dose regimens, or to high concentrations of the parent drug and/or its metabolite due to impaired systemic clearance and/or pharmacogenetic modulation of drug pharmacokinetics; (2) additive or synergistic effects of multiagent chemotherapy; (3) additive or synergistic effect of multimodality therapy that includes administration of chemotherapy either concurrently with or subsequently to cerebral radiation; (4) intra-arterial administration with blood–brain barrier disruption; and (5) intrathecal administration [12–17]. From the literature it is clear that not all patients are affected equally by chemotherapy. The finding that a subgroup of patients experience persistent post-treatment cognitive decline has led to the examination of patient- and disease-related risk factors for cognitive change. Candidate predictors of cognitive dysfunction frequently studied include age, education and pre-morbid IQ; however, no consistent predictors have been identified. Most studies failed to identify a relationship between treatment-related cognitive decline and age, IQ, education, baseline cognitive function and a host of other factors such as depression, anxiety, stress, fatigue, disease stage, haemoglobin levels and treatment-induced menopause. When an association between a sociodemographic or clinical predictor and cognitive dysfunction has been found the relationship is generally weak [3]. However, given the small sample sizes in nearly all studies, exploration of any sociodemographic or clinical predictors is likely to be underpowered. This is also the case for genetic factors (e.g.

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vulnerable alleles of genes such as APOE and COMT) that have been examined as potential risk factors for cognitive decline [5]. Risk factors – endocrine treatment: a treatment-related risk factor for cognitive decline in breast cancer patients that is of particular clinical relevance is the combined use of endocrine therapy. Breast cancer patients undergoing chemotherapy often receive endocrine therapy as well. These therapies commonly consist of treatment with selective oestrogen receptor modulators (SERMs) such as tamoxifen and/or aromatase inhibitors (AIs) such as exemestane, anastrozole or letrozole. Evidence derived from basic as well as clinical research indicates that estradiol, within a time window of opportunity, can stimulate neuroplasticity in brain areas involved in cognitive behaviour leading to improved performance [18–20]. Since SERMs and AIs also target brain areas involved in the regulation of cognitive behaviour, it is plausible that these substances may contribute to cognitive deterioration in breast cancer patients. Blocking estradiol synthesis with AIs deprives the brain of modulation via estradiol and therefore theoretically results in decreased neuroplasticity and impaired cognitive functioning. However, surprisingly, studies in breast cancer patients seem generally to indicate that AIs less consistently adversely influence cognitive functioning compared with SERMs [21]. Studies specifically addressing the interaction between chemotherapy and endocrine therapy are sparse and the majority of studies have been too small to adequately investigate this interaction. Absence of oestrogen neuroprotective action in the brain – in the natural, surgical or chemotherapy-induced postmenopausal brain – makes the brain possibly extra vulnerable to neural damage by chemotherapy [22]. Particularly in older breast cancer patients, treatment with SERMs seems to have a potentially detrimental effect on cognitive functioning [23]. Basic research is rather conclusive on the neuroprotective properties of SERMs in the absence of circulating estradiol, but the effects of chronic SERM administration on cognitive behaviour are more ambiguous. Cleary more research is needed, particularly on the effects of SERMs on the brain and behaviour in relation to age and the length of deprivation of endogenous estradiol. Risk factors – information: information on chemotherapyassociated cognitive problems is more and more accessible to patients. The reporting of cognitive problems may also be influenced by strictly cognitive mechanisms that are not rooted in psychological distress or negative affect, but simply in the extent to which a patient is informed about the possibility of cognitive problems following chemotherapy. Several studies on cognitive deficits in breast cancer patients showed that mere information about the association between chemotherapy and cognitive problems resulted in lower memory performance and higher complaint reporting [24,25]. These effects occurred independently of negative affect and preexisting knowledge. The notion that mere information can add to the occurrence and maintenance of cognitive problems is derived from a large body of social psychological research on stereotype threat and priming. Stereotype threat – i.e. fear of confirming a stereotype – has been researched extensively, and evidence shows that activation of a stereotype or schema

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unconsciously leads to behaviour that is in correspondence with that stereotype [26,27]. Concepts of stereotype threat and priming are important for explaining the effects of treatment-related information on complaint reporting and neuropsychological test scores. Furthermore, it may be that some individuals are particularly vulnerable to these effects. Research shows that stereotype threat effects are stronger among people who are especially cognizant of the particular stigma, and that participants who self-identify more strongly with a stereotyped group show stronger stereotype threat effects on cognitive function [28]. A recent study showed that receipt of stereotypical information about the occurrence of medical problems experienced by cancer patients primed the cognitive accessibility of the cancer patient stereotype and differentially affected women’s cognitive complaints and test scores, depending on their level of consciousness of cancer patient stigma [29]. It is not suggested that these psychological processes should be viewed as alternative explanations for biological influences. Rather, the possibility is raised that, for certain patients, self-regulatory and expectancy processes may also play a role – as a contributing, additive or meditational influence – in cognitive functioning. The next steps for clinical practice include the determination of the severity and duration of priming effects and to further understand the individual variation in these effects. In addition there is a need to explore the possibilities of diminishing or preventing these effects.

6. Neuropsychological studies in with central nervous system tumours

patients

Evaluating adverse effects of chemotherapy on cognitive function in CNS cancer patients is often challenging because of the variety of other factors that can impact cognition in this population, most notably treatment with radiation and tumour progression. Both radiation and chemotherapy have been reported to share at least one common mechanism for their adverse effect on brain and cognition: disruption of the neural stem and precursor cell function [30]. Only recently clinical trials have incorporated cognitive testing into their study design, providing the opportunity to address these issues in large samples of homogeneously treated patients. Radiation therapy has been demonstrated to adversely impact brain and cognition through vascular damage and inflammation, and via damage to neuronal progenitor cells affecting hippocampal neurogenesis and oligodendroglial formation [31]. Impairment in processing speed, attention, executive function and memory is commonly seen in brain tumour survivors previously treated with radiation therapy [32]. Several recent retrospective studies have examined the effects of radiation dose on different areas of the brain and cognitive outcomes. These studies provide evidence of a dose–response relationship between radiation to the bilateral hippocampal region and memory function [33], in addition to other brain regions and more heterogeneous cognitive outcomes [34]. Trials are currently under way in many centers to explore the use of technological advances in radiation

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delivery to spare normal tissues from radiation exposure, and to explore different forms of radiation such as proton therapy that may similarly achieve reduced-dose exposure to the normal brain and other critical structures. The standard of care for glioblastoma patients has included concomitant chemoradiation and adjuvant chemotherapy with temozolomide since 2004 [35]. A small singleinstitution study with standard-dose temozolomide reported cognitive decline in three out of 13 progression-free patients after concurrent chemoradiation and three cycles of adjuvant chemotherapy [36]. Declines were evident in psychomotor speed, attention and executive function, but not in verbal memory or working memory span. The results of a larger multi-institutional cooperative group trial comparing adjuvant standard-dose temozolomide and dose-dense temozolomide have also been reported [37]. In patients that were clinically and radiographically progression-free after concurrent chemoradiation and three cycles of adjuvant chemotherapy, 30% demonstrated cognitive decline, with no differences between arms. Cognitive decline was evident in all domains assessed – including verbal learning and memory, executive function and processing speed – and was prognostic of progression-free and overall survival. A recent study using temozolomide-administered rodents has demonstrated reduced hippocampal neurogenesis, decreased theta activity as measured by electromyography during an eye blink conditioning task and disrupted learning [38]. Due to the importance of angiogenesis in the growth and spread of cancer, there has been a great interest in inhibitors of vascular endothelial growth factor (VEGF), such as bevacizumab. Anti-VEGF agents have been demonstrated to produce rapid radiological improvement, ostensibly due to their ability to reduce tumour and blood–brain barrier permeability associated with leaky blood vessels. There is concern that this represents a ‘pseudoresponse’ which complicates the interpretation of traditional imaging end-points [39]. A phase II non-comparative study of bevacizumab in a recurrent glioblastoma multiforme (GBM) population included tests of cognition to characterise changes in brain function associated with bevacizumab therapy. In patients who achieved an objective radiographic response or who were clinically and radiographically progression-free at 24 weeks, the majority (75% and 70%, respectively) demonstrated stable or improved cognitive function relative to their pretreatment baseline [40]. Two placebo-controlled phase III trials with cognitive endpoints in newly diagnosed GBM patients are currently under way and will provide more information on the impact of bevacizumab on cognitive function. The long-term outcomes and associated reanalysis from the RTOG 9402 trial recently reported [41] a doubling of overall survival rates in pure or mixed anaplastic oligodendroglioma patients with 1p/19q co-deletion who received procarbazine, CCNU and vincristine (PCV) chemotherapy. This trial did not assess patient-oriented outcomes such as cognitive function to help determine the net clinical benefit of this survival advantage. However, two single-institution studies assessed cognition in anaplastic glioma [42] and GBM [43] patients treated with regimens that included PCV. Of patients with anaplastic glioma, 35% who were re-evaluated at a median of 8 months after initiation of treatment demonstrated cognitive

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decline. In GBM patients retested at a mean of approximately 8 months after initiating treatment, decreased cognitive function (in 44–52% of patients) was most commonly observed in the domains of psychomotor speed, executive function and memory. Unfortunately, these studies were not designed to distinguish the effects of chemoradiation from adjuvant chemotherapy and did not control for tumour progression, complicating the interpretation of these results as evidence of chemotherapy-related neurotoxicities. Cognitive dysfunction is a frequent presenting/occurring sign in patients with primary CNS lymphoma (PCNSL). However, unlike patients with primary brain tumours, many PCNSL patients who receive chemotherapy with or without radiation therapy show evidence of improvement in cognitive function [44]. For example, Correa et al [45] reported improvements in executive function and verbal memory up to 2 years after treatment in newly diagnosed PCNSL patients who were treated with induction rituximab, methotrexate, procarbazine and vincristine followed by reduceddose whole-brain radiation and consolidation high-dose cytarabine.

7. Neural mechanisms

substrate

and

underlying

Despite evidence of cognitive changes associated with chemotherapy in cancer patients, the pathophysiology of these changes needs further elucidation. Neuroimaging studies in breast cancer patients indicate structural changes in the brain associated with certain chemotherapeutic agents, and have started to shed light on the brain alterations that may be part of the mechanisms underlying the observed cognitive dysfunction in patients following administration of chemotherapeutic compounds without targeted CNS delivery.

8.

Imaging studies

Several structural imaging studies have been conducted among breast cancer patients treated with adjuvant regimens, with assessments generally occurring from months to 3 years after completion of treatment [46–50], although two studies examined patients 10 and 20 years after completion of treatment [51,52]. Nearly all of these studies are indicative of structural brain differences between patients that received chemotherapy and either healthy controls or breast cancer controls that did not receive chemotherapy. Whitematter pathology has been observed within months up to 10 years post-treatment, after both high-dose and standarddose regimens. Studies using voxel-based morphometry have reported volume reductions in white and grey matter 1 year to 20 years after completion of chemotherapy. A prospective study observed focal grey matter volume decrease 1 month after the cessation of chemotherapy, which recovered in some but not all regions at 1 year post-treatment. The cerebral white matter seems particularly vulnerable to the effects of chemotherapy. Studies investigating cerebral white matter integrity using diffusion tensor imaging (DTI) reported lower fractional anisotropy (FA) in the genu of the corpus callosum, lower FA in frontal and temporal white matter

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and higher mean diffusivity in frontal white matter of breast cancer patients who received standard-dose anthracyclinebased regimens compared with breast cancer controls and healthy controls. In a study conducted 10 years after completion of high-dose chemotherapy, DTI also showed lower FA in several white-matter tracts compared with breast cancer patients who never received chemotherapy [53]. In a large study conducted on average 20 years after completion of treatment, it was shown that in the absence of significant group differences in white matter integrity, time since treatment was inversely associated with lower global and focal white matter integrity within the breast cancer group [54]. This cross-sectional indication of affected white matter integrity was supported by a prospective study showing that breast cancer patients who received chemotherapy displayed significant decreases in FA in frontal, parietal and occipital white-matter tracts from pre- to post-chemotherapy, whereas for both a healthy control and a breast cancer control group, FA values were the same between baseline and follow-up [55]. Moreover there seems to be a link between the abnormal microstructural properties in white-matter regions and the cognitive impairments seen in breast cancer patients treated with chemotherapeutic agents; several studies observed correlations between abnormal diffusion properties and cognitive problems on neuropsychological testing [53]. The observed changes in DTI parameters may be related to demyelination of white matter axons or axonal injury after chemotherapy. Although caution is warranted in directly translating changes on structural imaging measures into biological changes, a rapidly increasing number of preclinical animal studies are helping define potential mechanisms underlying chemotherapy-induced cognitive dysfunction, and their results relate to a significant extent to the observations in human studies.

9.

Animal studies

Valuable insights have come from preclinical studies on the potential pathogenic mechanisms involved in cognitive impairment related to systemic administration of chemotherapeutic compounds without targeted CNS delivery, although the precise mechanisms remain insufficiently understood. Many factors have been proposed to play a role in chemotherapy-induced neurotoxicity, including the directly toxic effects of chemotherapeutic agents on various brain cells, vascular injury and the indirect immune-mediated inflammatory processes. It is unlikely that a single mechanism can explain much of the major cognitive problems observed in cancer patients following chemotherapy. Experimental studies have shown that many chemotherapeutic agents, when administered peripherally and in clinically relevant dosages, are associated with adverse effects on neurobiology and cognition (including 5-fluorouracil, methotrexate, doxorubicin, paclitaxel, cisplatin, BCNU and cyclophosphamide). In behavioural studies in animals, chemotherapy-related deficits have been observed in rodents on tasks that require involvement of the hippocampus and frontal systems. Toxicity is observed in multiple CNS cell types and multiple CNS regions [56]. Specifically, chemother-

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apy-induced damage of mature post-mitotic oligodendrocytes and immature progenitor cell populations required for ongoing neurogenesis, gliogenesis and maintenance of white matter integrity seems to be an important aetiological factor in the development of neurotoxicity [57]. Research focusing on the development of strategies to inhibit specific transporters to enable drugs to cross the blood– brain barrier (BBB) in sufficient amounts is also relevant for understanding the mechanisms by which chemotherapeutic agents not targeted to reach the CNS cause cognitive and brain changes. Gong et al. [58] propose in their stem-cell hypothesis that differential sensitivities of glioma stem cells and neural stem cells to alkylating agents, temozolomide, cisplatin and targeted agents such as erlotinib and bortezomib hold the key to the resistance of primary brain tumours and the occurrence of chemotherapy-associated neurotoxicity in non-CNS disease. The development of modalities that enhance delivery of drugs to brain tumours will also increase the drug exposure of the normal brain tissue, and may place patients at risk for treatment-induced cognitive decline. Until now, several preclinical studies have investigated pharmacological prevention strategies that further underscore the relevance of several hypothesised mechanistic pathways underlying the effects of chemotherapeutic agents on the brain and behaviour. Konat et al. [59] showed that N-acetyl cysteine, an antioxidant, ameliorated cognitive impairment in Wistar rats after combined administration of cyclophosphamide and doxorubicin. Two recent studies further explored potential candidates for interventions. A study by Lyons et al. [60] demonstrates that fluoxetine, when administered before and during treatment with 5-FU in rats, may prevent cognitive impairment and the loss of normal cell proliferation in the hippocampus observed after administration of 5-FU. Vijayanathan et al. [61] demonstrated that treatment with a glutamate receptor antagonist improved cognition after intrathecal administration of methotrexate in rats.

10.

Interventions

Cognitive dysfunction is a common consequence for many cancer patients, and it does not always fade away. As indicated, pharmacological interventions to prevent or intervene against cognitive symptoms are in an early stage of development. Agents that have been examined or that are currently under investigation in patients include erythropoietin, methylphenidate, modafinil, donepezil and melatonin [62,63]. Some of these agents are promising, but the need for their rigorous testing with appropriate study designs and sufficient sample sizes precludes translation and implementation in daily practice. Within the area of neuropsychological rehabilitation roughly two models can be distinguished: the restoration model and the compensation model [64]. The restoration model is directed at restoring damaged cognitive functions through function training, often using a so-called repeated practice approach, based on the assumption that specific stimulation induces plasticity. But evidence is still lacking that the benefits of training on specific tasks will transfer to

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other untrained tasks or lead to any general improvement in the level of cognitive functioning. Compensation techniques, on the contrary, are proven to be successful. Improvement in daily life functioning can be achieved using intact cognitive abilities and strategies. Neuropsychological rehabilitation based on the compensation model together with psycho-education and coping strategies can be offered to cancer patients confronted with cognitive problems to maximise their ability to function [65].

11.

Conclusion

Evidently, people with (a history of) cancer constitute an increasing group in our community. From this viewpoint, we have an obligation to obtain information on the cognitive effects of chemotherapy from a descriptive and preventive standpoint, and from an individual as well as a societal perspective. Chemotherapy is a necessary component in the management of many types of cancer, and the choices between different regimens in terms of adequate cancer control and minimal side-effects are restricted. Many cancer patients are returning to employment or other activities that may be affected by cognitive functioning. It is critical to identify cognitive effects of cancer treatment, to explore the mechanisms underlying these cognitive effects and to explore possible interventions that follow from these mechanisms and that may minimise cognitive side-effects and their severity and impact.

Conflict of interest statement None declared.

R E F E R E N C E S

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[28] Brown RP, Pinel EC. Stigma on my mind: individual differences in the experience of stereotype threat. J Exp Soc Psychol 2003;39:626–33. [29] Das E, Jacobs W, Monster S, Schagen SB. Priming cognitive problems following chemotherapy: the role of stigma consciousness. ICCTF Cong Cancer Conf 2012; March 15–17: Paris, France. [30] Gibson E, Monje M. Effect of cancer therapy on neural stem cells: implications for cognitive function. Curr Opin Oncol 2012;24:672–8. [31] Dietrich J, Monje M, Wefel J, Meyers C. Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy. Oncologist 2008;13:1285–95. [32] Wefel JS, Kayl AE, Meyers CA. Neuropsychological dysfunction associated with cancer and cancer therapies: a conceptual review of an emerging target. Br J Cancer 2004;90:1691–6. [33] Gondi V, Hermann BP, Mehta MP, Tome´ WA. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or lowgrade adult brain tumors. Int J Radiat Oncol Biol Phys 2013;85:348–54. [34] Peiffer AM, Leyrer CM, Greene-Schloesser DM, et al. Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline. Neurology 2013;80:747–53. [35] Stupp R, Mason WP, van den Bent MJ, et al. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–96. [36] Hilverda K, Bosma I, Heimans JJ, et al. Cognitive functioning in glioblastoma patients during radiotherapy and temozolomide treatment: initial findings. J Neurooncol 2010;97:89–94. [37] Wefel JS, Armstrong TS, Wang M, et al. Clinical utility of neurocognitive function as a prognostic factor for survival and measure of differential between-arm treatment effects on RTOG 0525. Presented at the 2011 Society for NeuroOncology Meeting in Collaboration with the AANS/CNS Section on Tumors. Orange County, CA; November 17–20, 2011. [38] Nokia MS, Anderson ML, Shors TJ. Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain. Eur J Neurosci 2012;36:3521–30. [39] Reardon DA, Galanis E, DeGroot JF, et al. Clinical trial end points for high-grade glioma: the evolving landscape. NeuroOncol 2011;13:353–61. [40] Wefel JS, Cloughesy T, Zazzali JL, et al. Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab. Neuro-Oncol 2011;13:660–8. [41] Radiation Therapy Oncology Group. RTOG 9402 finds chromosomal abnormality be a strong indicator for determining treatment and outcome for patients with oligodendroglioma brain tumors. Available at: . [42] Levin VA, Yung WKA, Bruner J, et al. Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV chemotherapy for the treatment of analplastic gliomas. Int J Rad Oncol Biol Phys 2002;53:58–66. [43] Groves MD, Maor MH, Meyers C, et al. A phase II trial of highdose bromodeoxyuridine with accelerated fractionation radiotherapy followed by procarbazine, lomustine, and vincristine for glioblastoma multiforme. Int J Rad Oncol Biol Phys 1999;45:127–35. [44] Correa DD, Maron L, Harder H, et al. Cognitive functions in primary central nervous system lymphoma: literature

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[62] Fardell JE, Vardy J, Johnston IN, Winocur G. Chemotherapy and cognitive impairment: treatment options. Clin Pharmacol Ther 2011;90:366–76. [63] Gehring K, Roukema JA, Sitskoorn MM. Review of recent studies on interventions for cognitive deficits in patients with cancer. Expert Rev Anticancer Ther 2012;12:255–69.

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[64] Cicerone KD, Langenbahn DM, Braden C, et al. Evidencebased cognitive rehabilitation: updated review of the literature from 2003 through 2008. Arch Phys Med Rehabil 2011;92:519–30. [65] Halligan PW, Wade DT. Effectiveness of rehabilitation for cognitive deficits. Oxford: Oxford University Press; 2005.

Drug-associated delirium in cancer patients Augusto Caraceni

*

Pain Therapy and Rehabilitation, National Cancer Institute of Milan, Italy European Palliative Care Research Center, Norwegian University of Science and Technology, Trondheim, Norway

1. Delirium characteristics

definition

and

clinical

Delirium is a disorder of consciousness and attention; it is one of the most common neurological complications seen in general in the medically ill hospitalised patient, and is also common in the medical oncology ward [1,2]. Delirium seen in different settings contributes to defining the diagnoses of diverse specificities: postoperative delirium, delirium in the ICU, withdrawal delirium or delirium tremens, terminal restlessness and others. Before considering specific clinical contexts or diagnoses it is necessary to recognise the general characteristics of delirium as a syndrome and its clinical implications. There is now almost universal agreement on the definition of delirium, or acute confusional state, according to the DSM. However, acute confusional state is a synonym of delirium and is still a useful clinical definition, particularly in nonEnglish-speaking countries. Delirium is a syndrome and not a disease, and its pathophysiology has not been fully elucidated. Different theories have favoured alternatively the failure of a common final pathway – mainly regulating the cholinergic projection to the cerebral cortex – or a more diffused or multifocal impairment of different areas in the CNS which contribute to maintaining the normal level of vigilance and attention. Clinically, delirium is an altered state of consciousness with reduced awareness of self and of the environment, which may present with inability to think and talk clearly and rationally; at times there are hallucinations, delusions, disorientation with respect to time and space, altered sleep– wakefulness cycle and cognitive impairment. Psychomotor agitation can be present in the hyperactive deliria, but hypoactive deliria will show psychomotor retardation and somnolence. One extremely important clinical aspect of delirium is fluctuation of the clinical presentation; symptoms can change suddenly, often under repetitive conditions (such as in the classic nocturnal worsening often described in the el-

derly with cognitive impairment and called in the past ‘sundowning’). These sudden changes from a near-to-normal mental state to frank delirium often surprise nursing and medical staff and find them unprepared in front of the patient and a distressed family. The clinical presentation of delirium varies, and no defined association of symptoms and signs can be considered specific [3]. For the purposes of diagnosis and clinical evaluation it is easier to use the DSM criteria as they give a systematic approach to the core clinical elements [4]. All four of the following criteria have to be fulfilled to make a diagnosis. Disturbance of consciousness (i.e. reduced clarity of awareness of the environment) with reduced ability to focus, sustain and shift attention; to fulfil this criterion the levels of both consciousness and attention need to be affected. Change in cognition (such as memory deficit, disorientation and language disturbances) or perception disturbances that are not better explained by a pre-existing established or evolving dementia. Testing cognitive function with simple bedside examinations such as the Minimental test is often enough to describe disorientation with respect to time and space, difficulties in performing calculations and in writing and simple memory tests. In the elderly with previous cognitive failure or being already demented it may be difficult to distinguish a failure in cognition as part of a chronic condition from a newly developing delirium (Table 1). Perceptual disturbances are illusions and hallucinations. Most often hallucinations are visual, but they are present only in a percentage of delirious patients and their absence is not a determinant for the diagnosis [3]. The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day. This criterion specifically aims to distinguish delirium from chronic conditions, particularly from dementia (Table 2), but in elderly patients with longstanding medical complications it may be difficult to differentiate the contribution of pre-existing neurological factors and incident acute factors. This distinction may be academic in

* Address: National Cancer Institute, Via venezian 1, 20133 Milano, Italy. Tel.: 39 02 23902792. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.008

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Table 1 – Main differential diagnoses of delirium. Clinical features

Delirium

Dementia

Acute psychosis

Onset Circadian course Level of consciousness Attention Cognition Hallucinations Delusions

Acute Fluctuating Affected Impaired Impaired Usually visual Poorly systematised and fleeting Increased, reduced mixed with alternating course Asterixis, myoclonus or tremor can be present in some subtypes Abnormala

Slow Stable Spared unless in severe cases Initially spared Impaired Often absent Often absent

Absent in most forms

Acute Stable Spared Can be impaired Can be impaired Often auditory Sustained and systematised Can vary, with bizarre behaviour depending on the psychosis Absent

Abnormala

Normal

Psychomotor activity

Involuntary movements

EEG

Often normal

EEG, electroencephalogram. *See text for more details.

Table 2 – Frequency of delirium in different patient populations admitted to hospital, hospice or home palliative care programme. Population

Prevalence (%) at admission

Incidence (%) during admission

Elderly P65 admitted to acute hospital unit Elderly P70 admitted to acute hospital unit Elderly P70 admitted to acute hospital unit Medical oncology unit Medical oncology unit Hospice Hospital palliative care unit Palliative care programme including home care Dying cancer patients in specialised palliative care unit

10.5

31.3 25.0 18.0 18.0 16.5

28.0 42.0 28.0

45.0 – 80

Modified from Caraceni and Grassi [2].

many cases but it is relevant, as described below, to explain many complex cases. Also in the case of advanced cancer patients, with multiple clinical problems and polypharmacy, delirium can be a long-lasting complication either characterising the final phase of the disease or being a reversible condition [5]. There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiological consequences of a general medical condition. This last criterion conceptually distinguishes delirium from primary psychiatric disease (mainly acute psychosis) (Table 1). In the old taxonomy this criterion was included in the construct of organic brain disorder or of recognising an organic cause of psychiatric symptoms. This terminology is no longer accepted by the latest DSM versions, but it can be used to clarify the scope of criterion 4. Based on the clinical presentation, delirium is distinguished into hypoactive, hyperactive and mixed types. The hyperactive deliria are usually associated with delusions and hallucination, disruptive or agitated behaviour and often worsening of symptoms during the night. Hypoactive deliria, in contrast, show a somnolent detached state of conscious-

ness and may be missed or mistaken for depression if the patient is not assessed more carefully with formal mental task testing. Mixed hyper- and hypoactive presentations are most frequent and the transition from hyperactive to hypoactive delirium, stupor and coma can be seen as one of the ways of dying.

2.

Frequency and assessment

The frequency of delirium is high in the acutely hospitalised patient population, with a prevalence which may be around 10% in the medical ward (excluding the cases of postoperative delirium). The most relevant patient populations seen by oncologists are summarised in Table 2, which shows that the frequency of this complication can not only increase in more advanced disease, but also that it is common in the elderly and as well as in the general oncology ward [6,7]. The diagnosis of delirium should be based on clinical observation and examination, and can be aided by the systematic use of screening tools to detect cognitive failure, such as the Minimental state examination, or tests specifically

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Table 3 – Diagnostic and etiological directions in case of delirium in the oncological patient (excluding postoperative delirium). Action

Assessment

Rule out structural brain lesions Rule out seizures, non-convulsive status epilepticus Rule out acute psychotic reactions

Oncological history, neurological examination, brain imaging if unclear When brain lesions are known or suspected EEG may be necessary

Identify potentially toxic agents Consider posterior reversible encephalopathy (MRI required) Reduce the risk of drug interactions Check metabolic factors and vitamin deficiency Think of rarer conditions

History of psychiatric disease, young age, psychogenic unresponsiveness or catatonia Specific (chemotherapy toxicity, brain RT, high-dose ifosfamide, antivirals, immunosuppressive agents) All generic psychoactive drugs Any drug can be involved; check metabolic pathways in the hepatic microsomal oxidising system Renal failure, hepatic failure, electrolyte imbalance, hypoxia, acidosis, B1 (thiamine) deficit Paraneoplastic neurological syndromes (usually associated with unknown or initial neoplastic disease)

EEG, electroencephalogram; MRI, magnetic resonance imaging; RT, radiotherapy.

designed to screen potential delirium cases, such the Nursing Delirium Screening Test (NuDESC). In the validation study by Gaudreau et al [8], the NuDESC proved sufficiently sensitive to be used as a screening tool in oncology, although recently a study on the detection of postoperative delirium in the elderly showed that sensitivity was too low in this population [9]. Still, a more careful and systematic approach [10] adopted by the nursing staff is a reasonable strategy and is to be recommended in oncology and particularly in palliative care settings such as a hospice. The diagnosis finally relies on the DSM criteria and requires specific expertise. The main differential diagnoses and their characteristics are listed in Table 1.

3.

Diagnostic procedures

As with any new neurological sign or symptom, in a patient with cancer a change in mental status requires a neurological examination and, if available, neurological consultation. In the case of neurological findings suggesting a structural brain lesion, imaging should be performed. In a patient with cancer, depending on the stage of the disease, it is not rare for delirium, even without focal neurological signs, to be an initial presentation of brain or meningeal metastases, as demonstrated in 15% of patients in one case series [11]. Encephalitis of infectious origin can occur particularly in immunocompromised patients and occurs not infrequently after bone-marrow transplantation conditioning chemotherapy. Cancer patients are at increased risk of posterior reversible encephalopathy syndrome (also known as posterior reversible leukoencephalopathy), a syndrome that is probably caused by damage to the brain vasculature and is found in association with immunosuppressive therapies (cyclosporine, tacrolimus), as a complication of transplant, high-dose multidrug chemotherapy (cytarabine, cisplatin, gemcitabine, vinorelbine, FOLFOX regimen and methotrexate) and of the new biological therapies such as anti-angiogenetic antibodies and others (bevacizumab, rituximab, bortezomid and motesanib) [12]. The syndrome usually includes seizures, cortical vi-

sual deficit and headache, but at presentation changes in mental status, or delirium, can dominate the clinical picture. When seizures are not associated with obvious generalised or focal convulsions, the differential diagnosis of delirium can be difficult. In fosfamide encephalopathy obtundation of consciousness and myoclonus reflect a continuous seizure-like activity in the electroencephalogram (EEG). Patients with a history of psychiatric disorders can develop acute psychotic reactions, especially when confronted with serious medical illness such as cancer, with clinical presentations such as unresponsiveness and catatonia that can be confused with delirium. These patients are usually young, and the clinical context helps to exclude the most common causes or risk factors of delirium. True paraneoplastic neurological syndromes presenting with altered mental state (limbic encephalitis) are indeed very rare; specific expertise is required for their diagnosis and they are usually found in association with initial cancer with the onset of the neurological syndrome preceding the diagnosis of cancer [13]. Table 3 summarises the elements which can guide clinical reasoning and a diagnostic strategy when faced with a cancer patient with delirium that is not occurring after surgery and general anaesthesia. The clinical context, risk factors, prognosis, associated symptoms and goals of care will influence the diagnostic path and completeness or futility of any interventions eventually required.

4.

Pathophysiology, risk factors and aetiology

The complex pathophysiology of delirium is beyond the scope of this chapter [14], but it is important to remember that the brainstem, thalamic and hypothalamic projections into the cortex are implicated in the regulation of normal vigilance and in modulating the level of consciousness between the physiological states of wakefulness and sleep. This system has a neurotransmitter organisation, including acetylcholine, dopamine, serotonin, histamine and c-aminobutyric acid

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Table 4 – Factors associated with the risk of developing delirium resulting from multivariate analysis in cancer. Modified from Caraceni and Simonetti [17]. Potentially specific predisposing factors: Advanced age Previously impaired cognition History of delirium Metastatic CNS lesion Non-specific factors associated with disease progression/ deterioration of general function: Functional impairment Severity of illness Low albumin Bone metastases Liver metastases Haematological malignancies Potentially specific incident factors: Metabolic abnormalities Metastases to brain or meninges Opioids (dose-related) Benzodiazepines Corticosteroids (dose-related)

(GABA). An imbalance in some of these neurotransmitters is thought to have a primary role in delirium pathophysiology. An impaired cholinergic transmission from the brainstem and enhanced dopaminergic tone are also thought to play a causal role in delirium [14]. All drugs with anticholinergic activity are sedating and can cause delirium. The cholinergic hypothesis can also explain the increased susceptibility to delirium of the elderly and of patients with cognitive impairment or dementia, considering that all these situations are characterised by a reduced function of the cholinergic central activating system. Delirium may have many causes, but in most cases a multifactor model can best explain its pathophysiology, with the combination of some predisposing conditions and incident noxious factors. This model was suggested by clinical observation in early studies on the syndrome [15] and has been confirmed by well-conducted cohort studies demonstrating that the combination of specific baseline conditions – such as advanced age, cognitive impairment, dementia and severity of illness – was associated with an increased incidence of delirium when combined with new factors, occurring during the hospital stay, in elderly patients [16]. Among incident factors, infections and medications were noted. The results, summarised in Table 4 [17], can be interpreted by classifying the associated factors such as structural lesion or functional abnormalities potentially impairing specific CNS functions (brain metastases, previous cognitive failure), being direct or indirect indicators of progression of the disease (metastases), or of poor general condition and toxic factors (benzodiazepines, opioids and steroids).

4.1.

The role of drug toxicity

Drug toxicity, in the setting of medical therapy or abuse, is an extremely frequent cause of delirium (Table 5). The ability to identify one drug as a cause for delirium depends on anecdotal clinical observation, pharmacological knowledge and

1 1 ( 20 1 3) 2 3 3–24 0

clinical studies. One recent systematic review of the literature supports the association of psychoactive medications, considered together, and use of opioids, which have an independent increased risk of developing delirium in cancer patients [18]. Another review focusing on patients at risk of developing delirium (elderly patients admitted to hospital for medical reasons or in the postoperative period) suggests avoiding the use of benzodiazepines in this population [19]. Experimental human studies demonstrated that anticholinergic drugs such as scopolamine, ditran and atropine can cause delirium depending on dosage [20]. Lower doses usually produce somnolence (scopolamine 0.3–0.8 mg), higher doses (atropine P5 mg, scopolamine = 1 mg) agitated florid delirium; paradoxical effects of low doses have also been demonstrated. In fact the list of drugs with anticholinergic activity is very long (Table 6), and such drugs should be used with caution, especially in the elderly with poor general conditions, multiple medical problems and polypharmacy. Unfortunately all these conditions are commonly found in cancer patients of advanced age, with progressive disease and who need appropriate palliative therapy for symptom control. Appropriate selection of drugs with simplified metabolic pathways and lack of interference would reduce the risk of adverse reactions.

4.2.

Opioids

Opioids are very important drugs for the quality of life of cancer patients, and their role in the management of pain and other symptoms cannot be underestimated. Opioids have CNS side-effects which include sedation, impairment of cognitive functions [21] and delirium. The central side-effects of opioids are usually dose-related and can be the main doselimiting side-effects in dose titration to obtain better pain control. High doses of opioids are associated with myoclonus, delirium, hyperalgesia and eventually seizures [22,23]. Symptoms of CNS toxicity can also occur at low doses in individual cases [24,25]. Recently an independent statistical association with the use of doses P90 mg of oral morphine per day was found to be associated with an increased risk of developing delirium [18]. This means that we have to carefully monitor the mental status of patients on significant opioid doses and seek for signs or symptoms of CNS toxicity such as myoclonus and hallucinations. Conversely, the mistake should not be made of blaming opioids for any complication. Most cases of delirium will be recognised in complex situations and with multiple factors together with, if not alternative to, opioid toxicity alone. Renal failure can make more difficult the choice of an opioid and increase the risk of delirium due to the accumulation of toxic metabolites. Drugs which exhibit the safest pharmacological profile, when renal failure occurs, are buprenorphine, fentanyl, alfentanil, remifentanil and sufentanil [26]. However, simple clinical measures include the choice of an opioid with least pharmacological interactions (morphine is the first choice), providing hydration if metabolite accumulation occurs because of reduced renal clearance, reduction of the dose and substitution of the opioid if toxicity is suspected. A palliative care consult is helpful to optimise opioid pharmacotherapy in these cases.

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Table 5 – Case reports of delirium associated with drug toxicity. Modified from Caraceni and Grassi [2]. Pychotropics: Clozapine Diphenydramine Fluoxetine Mianserin Promethazine Lithium Risperidone Antibiotics, antimalarials and antivirals: Ciprofloxacin Clarithromycin Mefloquine Ofloxacillin Acyclovir Gamcyclovir Drug combinations: Benzodiazepine/clozapine combination Flecainamide/paroxetine combination Diphenhydramine/linezolide combination Paroxetine/benztropine combination Lithium/neuroleptic combination Tacrine/ibuprofen interaction Ethanol/niacin coingestion Sertraline/haloperidol/benztropine combination H-2 receptor blockers: Famotidine (six cases) Ranitidine Ranitidine and cimetidine Opioids: Fentanyl Oxycodone Morphine Hydromorphone Antiblastic: Paclitaxel Vincristine Ifosfamide Cytosine arabinoside Cisplatin Methotrexate Thiotepa Etoposide Nitrosurea Biological drugs used in cancer: Bevacizumab Rituximab Other: Diet pills (phentermine) Amiodarone Cyclosporin Donepezil Herbal medicine loperamide, theales and valerian Levodopa Nizatidine Omeprazole Paclitaxel Steroids Tacrine Ziconotide Zolpidem

1 1 ( 2 0 1 3 ) 2 3 3 –2 4 0

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Table 6 – Drugs with anticholinergic activity in each category. The agents are listed from the more pronounced to less pronounced anticholinergic potency. Prototypical anticholinergics: Belladonna alkaloids Atropine Scopolamine Hyoscine butylbromide Robinul Antidepressants: Amytriptiline Imipramine Desimipramine Nortriptyiline Paroxetine Trazodone Mirtazapine Antihistamines: Marzine Diphenhydramine Promethazine Biperidene Trihexyphenidyl Cimetidine Ranitidine Neuroleptics: Chlorpromazine Flufenazine Clozapine Prochlorperazine Trifluorperazine Olanzapine Thioridazine Haloperidol Quetiapine Risperidoone Ziprasidone Anti-Parkinsonian: Amantadine, Levodopa Other: Metoclopramide Baclofen Entacapone

4.3.

Steroids

The use of steroids is very common in cancer patients. High doses and prolonged administration can induce delirium, also called in the past steroid psychosis [27]. Also sudden discontinuation of steroids can cause hypocortisol syndrome and delirium. It is very important that steroids are given for a limited amount of time and tapered slowly when no longer necessary. Usually at least a week or two of therapy is needed to develop psychiatric complications [28]. The symptoms can range from depression to mania and psychosis. The true incidence of mental changes related to steroid administration in palliative care is unknown. High doses are often reported to cause euphoria.

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4.4.

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Serotonin syndrome

when considering their use in combination with other serotonergic agents.

This significant toxic reaction became more frequent with the spread in the use of serotonin selective inhibitors (SSRIs, e.g. paroxetine) such as antidepressants. It is usually seen after the addition of a serotonergic drug to a drug regimen already containing serotonin-enhancing drugs, and it combines signs of encephalopathy (confusion, restlessness, myoclonus, hyper-reflexia, rigidity and coma) and of autonomic instability (fever, diaphoresis, diarrhoea, flushing, tachycardia, tachypnea, blood-pressure changes, midriasis, shivering and tremor). It may be fatal or may have a more benign course. Interactions of different drugs, often used in cancer patients, should be monitored (SRRI with tramadol, ketobemidone and venlafaxine). Table 7 lists a number of cases reported in the literature of drug combinations leading to serotonin syndrome. Caution should therefore be exercised not only in the use of the drugs reported but with all agents with serotonergic action, such as duloxetine and tapentadol, in particular

Table 7 – Serotonin syndrome reported in cases of administration of serotonin reuptake inhibitors alone or in combination with other serotoninergic substances. Drug

Combinations

Fluoxetine

Carbamazepine Pentazocine MAOIs Moclobemibe Nefazodone Tramadol Mirtazapine

Fluvoxamine

Alone Nefazodone Risperidone Moclobemide Isocarboxazide Nortriptyline Tranylcypromine Erythromycin Buspirone Loxapine

Paroxetine Sertraline

Tryptopan

1 1 ( 20 1 3) 2 3 3–24 0

Fluoxetine Non-selective MAOIs Clomipramine

Venlafaxine

Alone

Trazodone

Buspirone Nefazodone

Moclobemide

Citalopram Imipramine

Meperidine

Iproniazid MAOIs Moclobemide

Phenelzine

3,4-Methylenedioxymethamphetamine

Dextrometorphan

Non-selective MAOIs

Dothiepine

Alone

MOAIs, monoamine oxidase inhibitors.

4.5.

Drug pharmacological interactions

The role of metabolic interactions as a cause of toxicity is more and more likely as the number of drugs increase and the general patient condition deteriorates. The induction or inhibition of hepatic enzyme metabolism is an important source of variability in drug effects and can lead to unexpected toxic reactions. The P450 system comprises a family of more than 20 isoenzymes, among which the CYP 2D6 and the CYP 3A4 metabolise 80% of known drugs. A relatively recent review [29] reports on a number of examples of drugs commonly used in oncology and palliative care that have high or moderate probability of interacting with the same metabolic pathways and of leading to unexpectedly high or low levels of a drug, with the consequence of under- or over-dosing; examples of such drugs include methadone, codeine, oxycodone, haloperidol, tricyclic antidepressants (TCAs), SSRIs, monoamine oxidase (MAO) inhibitors, benzodiazepines, macrolides, azoles, rifampin and antifungals. Table 8 shows a list of interactions that can be particularly relevant in the management of symptoms in cancer patients. However, the clinical role of drug interaction in producing specific effects may be very difficult to ascertain; laboratory in vitro data may not be applicable to the clinical situation, while in vivo other circumstances may be operating to change the effect that was expected on the basis of laboratory data. For instance, in dogs the co-administration of ketoconazole and midazolam resulted as expected in a reduced elimination of midazolam but did not affect the elimination of fentanyl [30]. Case reports suggest that these interactions are indeed at times important [31,32].

Table 8 – Potential drug interactions with potential elevation of blood plasma levels of central nervous system active agents. CYP2D6 inhibitors

Drugs metabolised by CYP2D6 whose plasma levels can increase when combined with inhibitors

Cimetidine Desimipramine Fluoxetine Paroxetine Haloperidol Sertraline

Oxycodone Tramadol Haloperidol Risperidone Fluoxetine Paroxetine Venlafaxine Desimipramine

CYP3A4 Inhibitors

Drugs metabolised by CYP3A4 whose plasma levels can increase when combined with inhibitors

All imidazole antifungals Fluoxetine Norfloxacine

Fentanyl Alfentanyl Methadone Alprazolam Midazolam

EJC SUPPLEMENTS

The number of potential pharmacological interactions is extremely large and variable according to clinical conditions and antineoplastic, supportive and combined therapies. Dexamethasone, anticonvulsants and cisplatin or asparaginase have specific interactions, to give only one example. In cases of delirium, a specific review of drugs and their metabolism is mandatory. Conversely the choice of drugs with the least metabolic interference potential is to be recommended. Guidelines to treat pain and depression, for instance, should recommend as first choice morphine, mirtazapine or citalopram, while TCAs should not be used as first choice in combination with morphine because of their strong anticholinergic effects and also because they increase morphine bioavailability [33]. However, oral gabapentin has been shown to increase oral morphine bioavailability [34], but the clinical impact of this observation has never been clarified.

4.6.

Alcohol and drug withdrawal

Patients with known alcohol and or drug abuse, in particular chronic use of benzodiazepines, should be considered at risk ofwithdrawalin thecaseofreduced orsuspended intakeofalcohol when admitted to the hospital or hospice. Alcohol withdrawal delirium should be treated with benzodiazepines; in severe cases (delirium tremens) this can be life-threatening and requires specialist advice or intensive care. More subtle cases can result from the sudden discontinuation of the chronic use of benzodiazepines in patients with reduced ability to swallow when admitted to a care facility, which may go unnoticed without a very careful assessment of the patient history.

4.7. Delirium as a complication of the terminal phase of advanced cancer In patients with advanced cancer undergoing palliative care and admitted to a hospice, delirium episodes are particularly frequent; this can be expected from the progressive accumulation of the risk factors described, and indeed the prevalence of delirium tends to increase as the terminal phase of illness approaches, reaching 80% in the last days of life, and it is per se a prognostic factor of shortening life expectancy [7,35]. On the other hand, in palliative care units and in hospices delirium episodes can be reversible – owing to modifiable etiologies, such as drugs and infections – in as many as 50% of the cases [5,36]. It is therefore of extreme importance to assess delirium reversibility in advanced disease, to direct treatment goals and family counselling. When a single drug toxicity can be identified the probability of reversing toxicity is also high [36], but on the other hand when the clinical situation is complex – due to multiple concurrent factors, organ failure and in an advanced phase of the disease – reversibility is less likely and delirium can be viewed as one aspect of the terminal phase of the illness. In this last case, not only can it be impossible to modify the eventual contribution of drugs to the delirious state, it could also be futile or even inappropriate if comfort and quality of dying is the goal of care. Interventions directed at dealing with and managing the impact of delirium on family distress and anxiety are particularly appropriate at this time [37].

1 1 ( 2 0 1 3 ) 2 3 3 –2 4 0

5.

239

Delirium management

Screening of potential etiologies, starting with an accurate medication list, is the first step in delirium management; consequently a first recommendation is to withdraw all medications that are not absolutely necessary. Very often finding the aetiology is delayed, and the time to recovery after modifying etiological factors can be significant. In a number of cases, as already discussed above, the multifactor pathophysiology can be part of a complex clinical picture which does not allow for recovery or is even part of the dying process. All of these conditions require symptomatic management – in particular to control hallucinations, delusions and psychomotor agitation – be it temporary until recovery or continuously until death. The first-line pharmacological intervention for delirium is neuroleptics, and haloperidol is the first-choice drug according to all clinical guidelines [38–41]. In patients with mild to moderate delirium, oral medication may be indicated, but more difficult cases will require parenteral administration. Haloperidol initial dose can vary from 0.5 to 1 mg, orally or parenterally b.i.d., according to patient age, and should be titrated in the following hours depending on the severity of delirium symptoms. Titration of the dose is a fundamental step before a real lack of clinical response can be documented, as many treatment failures are failing this recommendation. Parenteral haloperidol can be used via intramuscular administration. This can be necessary in patients without an IV line and with very disruptive behaviour, otherwise an IV infusion can also be adopted. The use of haloperidol should be preceded by cardiac monitoring with electrocardiography (ECG), according to some national regulations, while its intravenous infusion is not officially approved, although commonly used in different settings of care. Prolongation of the Q–T interval on the ECG may contraindicate the use of haloperidol. This caveat is based on reports of cases of fatal cardiac arrhythmia following haloperidol administration. Pharmacological treatment of delirium aims at patient tranquilisation, abolishing hallucinations and delusions, reducing psychomotor agitation, and improving night-time sleep. Haloperidol, risperidone or olanzapine, while sharing a strong tranquilising action, are not primarily sedating drugs and haloperidol has the least sedating properties among all the neuroleptics. If required, more sedating neuroleptics can be used: for example quetiapine (25–50 mg b.i.d.), eventually giving a higher dose at bed-time. If this approach fails, more specific drugs can be added to control symptoms by keeping the patient sedated, including antihistamines, benzodiazepines and eventually alfa-2 agonists (clonidine, dexmedetomidine). All these regimens require specialist advice, be it from the neurologist, psychiatrist or palliative medicine consultant, depending on the clinical conditions and setting [17].

6.

Conflict of Interest

The author has no conflict of interest relating to this article.

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[1] Caraceni A, Scolari S, Simonetti F. The role of the neurologist in oncology a prospective study. J Neurol 1999;246(Suppl. 1). I/ 68. [2] Caraceni A, Grassi L. Delirum: acute confusional stated in palliative medicine. 2nd ed. Oxford: Oxford University Press; 2011. [3] Meagher DJ, Moran M, Bangaru R, et al. Phenomenology of delirium. Assessment of 100 adult cases using standardized measures. Br J Psychiatry 2007;190:135–41. [4] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th edition. Text revision. DSM IV-TR. Washington: American Psychiatric Press; 2000. [5] Leonard M, Raju B, Conroy M, et al. Reversibility of delirium in terminally ill patients and predictors of mortality. Palliat Med 2008;22:848–54. [6] Ljubisavjevic V, Kelly B. Risk factors for development of delirium among oncology patients. Gen Hosp Psychiatry 2003;25:345–52. [7] Hosie A, Davidson MP, Agar M, Sanderson CR, Phillips J. Delirium prevalence, incidence, and implications for screening in specialist palliative care inpatient settings: a systematic review. Palliat Med 2012;27:486–98. [8] Gaudreau J, Gagnon P, Harel F, Tremblay A, Roy M. Fast, systematic and continuous delirium assessment in hospitalized patients: the nursing delirium screening scale. J Pain Symptom Manage 2005;29:368–75. [9] Neufeld K, Leoutsakos J, Sieber F, et al. Evaluation of two delirium screening tools for detecting post-operative delirium in the elderly. Br J Anaesth 2013. http://dx.doi.org/ 10.1093/bja/aet167. [10] Gaudreau J, Gagnon P, Harel F, Roy M. Impact on delirium detection of using a sensitive instrument integrated into clinical practice. Gen Hosp Psychiatry 2005;27:194–9. [11] Tuma R, DeAngelis LM. Altered mental status in patients with cancer. Arch Neurol 2000;57:1727–31. [12] Staykov D, Schwab S. Posterior reversible encephalopathy syndrome. J Int Care Medicine 2012;27:11–24. [13] Graus F, Dalmau J. Paraneoplastic neurological syndromes. Curr Opin Neurol 2012;25:795–801. [14] Gaudreau J, Gagnon P. Psychotogenic drugs and delirium pathogenesis: the central role of the thalamus. Med Hypotheses 2005;64:471–5. [15] Lipowski ZJ. Etiology. Delirium: acute confusional states. New York, Oxford: Oxford University Press; 1990. p. 109–40. [16] Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 1996;275:852–7. [17] Caraceni A, Simonetti F. Palliating delirium in patients with cancer. Lancet Oncol 2009;10:164–72. [18] Gaudreau J, Gagnon P, Roy M, Tremblay A. Psychoactive medications and risk of delirium in hospitalized cancer patients. J Clin Oncol 2005;23:6712–8. [19] Clegg A, Young J. Which medications to avoid in people at risk of delirium: a systematic review. Age Ageing 2011;40:23–9. [20] Itil T, Fink M. EEG and behavioral apects of the interaction of anticholinergic hallucinogens with centrally active compounds. Prog Brain Res 1968;28:149–68. [21] Kurita G, Lundorff L, Pimenta C, Sjøgren P. The cognitive effects of opioids in cancer: a systematic review. Support Care Cancer 2009;17:11–21.

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[22] Hagen N, Swanson R. Strychnine-like multifocal myoclonus and seizures in extremely high-dose opioid administration: treatment strategies. J Pain Symptom Manage 1997;14:51–8. [23] Okon T, George M. Fentanyl-induced neurotoxicity and paradoxic pain. J Pain Symptom Manage 2008;35:327–33. [24] Caraceni A, Martini C, De Conno F, Ventafridda V. Organic brain syndromes and opioid administration for cancer pain. J Pain Symptom Manage 1994;9:527–33. [25] Bruera E, Schoeller T, Montejo G. Organic hallucinosis in patients receiving high doses of opiates for cancer pain. Pain 1992;48:387–99. [26] King S, Forbes K, Hanks G, Ferro C, Chambers E. A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project. Palliat Med 2011;25:525–52. [27] Breitbart W, Stiefel F, Kornblith AB, Pannullo S. Neuropsychiatric disturbance in cancer patients with epidural spinal cord compression receiving high dose corticosteroids: a prospective comparison study. Psychooncology 1993;2:233–45. [28] Stiefel FC, Breitbart WS, Holland JC. Corticosteroids in cancer: neuropsychiatric complications. Cancer Invest 1989;7:479–91. [29] Bernard SA, Bruera E. Drug interactions in palliative care. J Clin Oncol 2000;18:1780–99. [30] KuKanich B, Hubin M. The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs. J Vet Pharmacol Ther 2010;33:42–9. [31] Levin TT, Bakr MH, Nikolova T. Case report: delirium due to a diltiazem–fentanyl CYP3A4 drug interaction. Gen Hosp Psychiatry 2010;32(648):e9–e10. [32] Tsao Y, Gugger J. Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. Ann Pharmacother 2009;43:1366–9. [33] Ventafridda V, Ripamonti C, DeConno F, et al. Antidepressants increase bioavailability of morphine in cancer patients (letter). Lancet 1987;1:1204. [34] Eckhardt K, Ammon S, Hofmann U, et al. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg 2000;91:185–91. [35] Scarpi E, Maltoni M, Miceli R, et al. Survival prediction for terminally ill cancer patients: revision of the palliative prognostic score with incorporation of delirium. Oncologist 2011;16:1793–9. [36] Lawlor PG, Gagnon B, Mancini IL, et al. Occurrence, causes and outcome of delirium in patients with advanced cancer. Arch Intern Med 2000;160:786–94. [37] Morita T, Hirai K, Sakaguchi Y, Tsuneto S, Shima Y. Familyperceived distress from delirium-related symptoms of terminally ill cancer patients. Psychosomatics 2004;45:107–13. [38] Lonergan E, Britton A, Wyller T. Antipsychotics for delirium. Cochrane database of systematic reviews; 2007:Art.No:CD005594. doi: 10.1002/14651858.CD005594. [39] National Guidelines for Seniors’ Mental Health: The Assessment and Treatment of Delirium. ; 2006. (accessed 03.05.08). [40] Casarett D, Inouye S. Diagnosis and management of delirium near the end of life. Ann Intern Med 2001;135:32–42. [41] Cook IA. Guideline Watch. Practice guideline for the treatment of delirium. Am Psych Assoc; 2004. Available from .

Introduction

Lung cancer in non-smokers Rolf A. Stahel Klinik fu¨r Onkologie, Universita¨tsspital, Zu¨rich, Switzerland

The decrease in lung cancer mortality in many Western societies is being attributed to a large extent to smoking prevention measures. However, lung cancer also occurs in nonsmokers, with an estimated frequency of 10–25%. The identification of oncogenic driver alterations which are successfully targetable, being more prevalent in lung cancer in non-smokers, has encouraged interest in these tumors. The current knowledge on the molecular alterations in lung tumors of patients who have never smoked is summarised in the article of Drs. Subramanian and Govindan. Smoking prevention is of

particular importance for pregnant women. The effect of inutero exposure to tobacco smoke is a growing area of research in the field of passive smoking. Current knowledge on its potential health consequences is summarised by Dr. Nawroth and colleagues.

Conflict of interest statement None declared.

1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.002

Prevention – Passive smoking and pregnancy Tim S. Nawrot *, Bianca Cox, Bram G. Janssen, Michelle Plusquin Centre for Environmental Sciences, Hasselt University, Belgium Leuven University, Department of Public Health & Primary Care, Belgium

1.

Introduction

Epidemiological studies have demonstrated that tobacco smoke is a major cause of both cancer and vascular diseases. More than 3800 chemicals are present in tobacco smoke, which may cause oxidative stress via biotransformation or by macrophage activation. In 1954, Richard Doll and Bradford Hill published the first prospective evidence on cigarette smoking and lung cancer [1,2]. In 1962, Framingham investigators published data showing that smoking increased the risk of heart disease [3]. Nevertheless, despite the strong evidence, uncertainty was manufactured and enlarged. This strategy is a common practice to reduce the public health implications from epidemiological findings and was used not only by tobacco companies but also by other industrial arms, including asbestos and lead factories [4]. For almost half a century, the tobacco companies hired scientists to dispute first that smokers were at greater risk of dying of lung cancer; second, the role of tobacco use in heart disease; and finally, the evidence that environmental tobacco smoke increased disease risk in non-smokers [5,6]. The effect of in-utero exposures on health in childhood and later in life is a growing area of research interest, with major public health implications. Children are vulnerable to the adverse effects of environmental tobacco smoke as their lungs and immune system are undergoing further development. The first publications of detrimental health effects of parental smoking on children’s respiratory health were published in the early 1970s [7]. Exposure to environmental tobacco smoke in the first 2 years of life has been estimated in some European countries by Pattenden et al. [8] and ranged from 19% in Germany to 70% in Bulgaria.

2. Meta-analytical effects

evidence

of

early-life

There is pooled evidence that constituents of cigarette smoke cross the placenta, induce pregnancy complications, reduce

intrauterine foetal growth and increase the risk of preterm delivery (Table 1) [9,10]. Meta-analytical evidence has also shown increased risk of respiratory and ear infections [11–13], overweight [14]and an increase in blood pressure [15] in early life and/or childhood, suggesting that maternal smoking in pregnancy influences the foetal development of different organ systems. Indeed, low birth weight and preterm delivery are also determinants of health risks later in life, including childhood asthma [16,17]. A cross-sectional study of 11,500 participants of 8–11-year-old children showed that prenatal exposure to cigarette smoke has a stronger effect on childhood asthma compared with postnatal smoke [18]. Prenatal exposure to maternal smoking without subsequent postnatal exposure to environmental tobacco smoke was related to the presence of asthma at school age with an odds ratio (OR) of 1.8 (95%CI: 1.1–2.9) [18]. Parental smoking increases the risk of acute lower respiratory tract diseases in children [12,13]. The pooled estimates showed a higher risk in association with smoking by the mother (OR: 1.56, 95%CI: 1.51–1.62) than with smoking by the father (OR: 1.31, 95%CI: 1.20–1.42) [12]. The higher risk related to the mother’s smoking could be explained by the fact that young children usually spend more time with their mother or by the interplay with maternal smoking during pregnancy. In addition to lower respiratory tract infections (OR: 1.51 95%CI: 1.44–1.52), exposure to environmental tobacco smoke has been associated with an increased risk of otitis media (OR: 1.32, 95%CI: 1.14–1.52) [12]. Exposure to prenatal tobacco increases the level of genetic damage in newborns and children. A meta-analysis performed in children exposed to environmental tobacco smoke showed that children and newborns had, respectively, 1.3 and 6.7 times higher levels of haemoglobin adducts compared with non-exposed newborns [19]. Available meta-analytical evidence of an association between in-utero exposure to tobacco smoke from the parents and childhood cancer seems weak. Maternal smoking was estimated as an increased risk

* Corresponding author. Address: Centre for Environmental Sciences, Hasselt University, Agoralaan building D, 3590 Diepenbeek, Belgium (T.S. Nawrot). Tel.: +32 11 268382; fax: +32 11 268299. E-mail address: [email protected] (T.S. Nawrot). 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.003

Table 1 – Meta-analytical evidence of early-life exposure to cigarette smoke. Author/Year (population)

Design

N articles

N

Pooled Estimate

Placenta previa

Castles et al. [9] (North America, Western Europe)

Case–control Cohort

6

50.695 Patients

1.58 (1.04–2.12)a

57.302 10.632 34.668 4.451 Cases: >100.000

1.62 (1.46–1.77)a 1.77 (1.31–2.22)a 1.7 (1.18–2.25)a 0.51 (0.38–0.64)a 1.27 (1.21–1.33)a 0-10 Cig/Day: 1.25 (1.12–1.38)a 11-20 Cig/Day: 1.38 (1.23–1.55)a >1 Pack/Day: 1.31 (1.19–1.45)a Paternal smoking during pregnancy1.17 (0.96– 1.42)b Paternal smoking around the time of conception1.15 (1.06–1.24)a Smoking by Either Parent0.99 (0.70–1.40)a

Abruptio placenta Ectopic pregnancy Preterm PROMc Pre-eclampsia Preterm delivery (>32 weeks but 1 when exposure is associated with a decreased level of the investigated biomarker. e SCE: sister chromatid exchange is the exchange of genetic material between two identical sister chromatids. The reason for the SCE is not known but it is required and used for mutagenic testing of many products. Four to five sister chromatid exchanges are in the normal distribution, 14–100 exchanges are not normal and present a danger to the organism. f Primary analysis of overweight has been chosen, defined as BMI P85th percentile or P90th percentile for age and sex. b

1 1 ( 20 1 3) 2 4 2–24 7

Respiratory tract infections

Lower respiratory illnesses Smoking by either parent: 1.51 (1.44–1.59)a Maternal smoking: 1.56 (1.51–1.62)a Paternal smoking: 1.31 (1.20–1.42)a Hospitalisation for respiratory illness 1.93 (1.66–2.25)a Serious infections0–2 years: 1.71 (1.33–2.20)a 3-6 years: 1.25 (0.88–1.78)a Maternal smoking during pregnancy 1.03 (0.90–1.17)

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Moritsugu et al. [12] (Europe, North America, Australia, Asia, Africa)

244

Lower respiratory illnesses

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of 10% (95%CI: 1.03–1.19) for childhood cancer, yet no significant elevated risk was found for lymphomatic and haematopoietic neoplasm, or for cancer of the central nervous system or kidney cancer (Table 1) [20]. When considering maternal and paternal in-utero exposure to genotoxic compounds, a difference in the mode of action is implied in the direct transplacental effects versus the preconception alterations. Carcinogens in tobacco can induce DNA damage in sperm: male smokers have higher levels of 8-oxo-2-deoxyguanosine in their semen than non-smokers, which may result in oxidative damage to sperm DNA [21,22]. Paternal smoking during conception and acute lymphoblastic leukaemia are related with a pooled odds of 1.15 (CI: 1.06–1.24), paternal exposure during pregnancy is not [20,23]. Furthermore, meta-analytical work suggests an increased risk after paternal exposure to tobacco smoke with childhood non-Hodgkin lymphoma and tumors in the central nervous system [20]. Based on pooled evidence of 25 studies [24], maternal smoking was associated with almost a 4-fold time increase in risk of sudden infant death syndrome. The corresponding risk of paternal smoking with absence of maternal smoking was 1.49 (Table 1). While the effect of smoke exposure in utero seems to be stronger, postnatal environmental tobacco smoke has been found to increase the risk of sudden infant death syndrome even after controlling for prenatal exposure. However, in most cases this is difficult to distinguish as most children that have been exposed in utero are also exposed during their first months of life.

3.

Smoking ban and health gains

The positive effect of smoking cessation suggests a causal association between active smoking and cardiovascular disease [25]. Evidence from observational studies shows a decrease in cardiovascular events in progression of atherosclerosis in those who quit smoking compared with those continuing to smoke cigarettes. Along with this, evidence from cohort studies and ecological evidence on recent smoking bans (introduced by law) consistently shows a rapid decrease in hospitalisation for myocardial infarction (MI). The pooled aggregated data showed that the rate of acute MI hospitalisation in countries that implemented a smoking ban law, decreased 12 months after its implementation, on average by 17% (95%CI: 20–13%) [26]. The rapid decrease in MI after introduction of bans suggests an interplay between chronic and acute processes, including triggers. A trigger can be defined as an external stimulus that produces acute physiological or pathophysiological changes. The idea of the pathophysiological relevance of triggers leading to the onset of acute myocardial infarction (MI) has been proposed [27]. In general, ageing leads to functional and structural abnormalities of the arterial wall, which are amplified by hypertension and atherosclerosis [28]. A vulnerable atherosclerotic plaque might lead to an occlusive thrombus which is more likely to be formed if other factors come into play to narrow homoeostasis and increase vasoconstriction. The role of triggers such as alcohol [29], anger [30,31], physical exertion [31,32]and use of marijuana [33] in the onset of MI is recognised [34]. Recently gained evidence supports the notion that premature birth is also a syndrome which might have trigger components, including ambient temperature and smoking

1 1 ( 2 0 1 3 ) 2 4 2 –2 4 7

245

[35,36]. Recent Scottish [36] and Belgian [35] data support reductions in the rate of preterm births after the implementation of smoking bans, whereas no such decrease was evident in the years or months before these bans. In Belgium, smoke-free legislation was implemented in different phases (in public places and most workplaces in January 2006, in restaurants January 2007, and in bars serving food January 2010). We were able to demonstrate a consistent pattern of changes in preterm delivery with stepwise reductions over the different enforcements. In an analysis using a birth register comprising 606,877 live-births, we observed an immediate change in the risk of spontaneous preterm delivery of 3.13% (95%CI: 4.37% to 1.87%; P < 0.01) on 1st January 2007 (ban on smoking in restaurants), and an annual slope change of 2.65% ( 5.11% to 0.13%; P = 0.04) after 1st January 2010 (ban on smoking in bars serving food). In 716,941 Scottish newborns, the risk was decreased by 11.72% (95% CI: –15.87 to –7.35) 3 months prior to the introduction of the comprehensive smoking ban in 2006. Similarly to Belgian findings, a study on the impact of the Irish workplace smoking ban on birth weight and preterm birth found a protective effect only on the latter outcome [37]. Although their analysis was limited to a comparison of rates 1 year before and after the ban, they even found an increase in the risk of low birth weight. The smoking ban studies must be viewed as an investigation of the possible impact of a ‘population intervention’ rather than an investigation of changes in individual behaviour. It is possible that unmeasured confounders were responsible for the observed changes. Nevertheless, it is hard to conceive of a factor that could change the population risk of preterm births after the introduction of the different successive smoking bans. It is unlikely that our observations could be explained by abrupt changes in therapeutic strategies coinciding with the smoking bans. Nevertheless, the Belgian study collected data on the prescription of atosiban and on cervical cerclage treatment from a social security organisation covering 42% of the population. Atosiban is an inhibitor of oxytocin and vasopressin and is specifically used to halt premature labour. Cervical cerclage is used for the treatment of cervical incompetence, a condition where the cervix has opened slightly and there is a risk of miscarriage. Given that even a mild reduction in gestational age has been linked to adverse health outcomes in early and later life, these population interventions have important public health implications. Indeed, a Swedish study found that, even among those born late preterm (34–36 weeks), preterm birth was associated with a 31% (13–50%) increase in mortality in young adulthood [38].

4.

Molecular epidemiological aspects

The human placenta forms the interface between foetal and maternal circulation, and by controlling nutrient supply plays a critical role in the regulation of foetal growth and development. Maternal smoking causes perturbations in this uteroplacental exchange as it increases the risk of low birth weight [39,40] and preterm delivery [35,41]. The mechanisms underlying these observed effects remain unclear, but emerging data suggest that biochemical, genetic and epigenetic activi-

246

EJC SUPPLEMENTS

1 1 ( 20 1 3) 2 4 2–24 7

ties respond to and are modified by in-utero tobacco exposure. Nutrients and potential pollutants are metabolised, making the placenta a molecular ‘footprint’ to which the foetus has been exposed in utero. Mitochondria are abundant in placental cells, they provide energy for the functioning of this metabolically active organ. Each cell contains approximately 200–2000 mitochondria, carrying between two and ten copies of mitochondrial DNA (mtDNA). Recently, by assessing the relative mtDNA content (a marker of mitochondrial damage and dysfunction), its functioning has been linked to various disease mechanisms [42,43]. The placental mtDNA content has been shown to be very adaptive to environmental insults, including maternal smoking [44] and air pollution [45]. The relative mtDNA content is decreased by 37% (P < 0.02) in placentas of mothers who smoke [44] compared with a decrease of 17.4% (P = 0.05) for each 10-lg/m3 increase in PM10 exposure during the third trimester of pregnancy [45]. Important questions remain concerning how mitochondrial biogenesis and maintenance are regulated as a response to tobacco exposures, and how these relate to placental functioning. An attractive link between adverse insults and altered foetal development is gene regulation. Maternal smoking during pregnancy can lead to changed placental gene expression levels, which is epigenetically regulated by DNA methylation, histone modifications or non-coding RNAs. Epigenetic changes can occur throughout the course of life as a result of environmental conditions. Much of the epigenome is already established in germ cells and embryos as it appears to be particularly important for the regulation of embryonic growth and placental development [46]. Recently, studies investigating cord blood and placental tissue showed that the epigenetic system is sensitive to tobacco exposure in utero. Global DNA methylation levels in cord blood is lower among newborns with smoking mothers (mean = 15.04%; 95%CI: 8.4–21.7) compared with second-hand smokers (21.1%; 95%CI: 16.6, –25.5) and their non-smoking counterparts (mean = 29.2%; 95%CI: 20.1–38.1) [47]. An epigenomewide methylation study in cord blood of newborns exposed to tobacco smoke during pregnancy showed that genes that play an important role in detoxifying components of tobacco smoke (AHRR and CYP1A1) are differentially methylated [48]. Accordingly, Suter and colleagues reported site-specific changes in DNA methylation of the CYP1A1 promoter, and this hypomethylation correlated with an increase in CYP1A1 gene expression in the placenta [49]. They showed in an epigenome-wide methylation study on placental tissue that methylation levels of 623 genes are deregulated in a CpG site-specific manner [50]. Despite a limited number of (epi)genomic studies in cord blood and placental tissue, we are getting a better picture of how maternal tobacco smoke can alter placental functioning and contribute to adverse pregnancy outcomes. Therefore the potential health consequences of changes in mitochondrial functioning, gene expression and epigenetics in early life should be further elucidated.

R E F E R E N C E S

Conflict of interest statement None declared.

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Molecular profile of lung cancer in never smokers Janakiraman Subramanian a, Ramaswamy Govindan a b c

b,c,*

University of Tennessee Medical Center, Department of Medicine, Knoxville, USA Washington University School of Medicine, Department of Medicine, St. Louis, USA Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis, USA

A R T I C L E I N F O

Tobacco smoking is the most common cause of lung cancer, but approximately 10–25% of patients with lung cancer are life-long never smokers. The cause of lung cancer in never smokers is unknown, although tobacco-smoke exposure may play a role in some of these patients. Lung cancer that develops in the absence of significant tobacco-smoke exposure appears to be a unique disease entity with novel genomic and epigenomic alterations and activation of molecular pathways that are not generally seen in tobacco-smoke-induced lung cancer. These molecular alterations are very likely responsible for the unique clinico-pathological features of lung cancer in never smokers (LCINS), and some of these molecular alterations – such as the activating EGFR TK mutations and EML4–ALK fusion – significantly influence therapeutic choices and treatment outcomes. In the last few years there has been a number of studies exploring the molecular characteristics of LCINS, and some of them have reported new and significant findings. Here we review the key findings from these studies and discuss their potential therapeutic implications. Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved.

1.

Introduction

Globally, over a million patients are diagnosed with lung cancer each year, making it the most common type of cancer in the world [1]. Even though tobacco smoking is considered to be the most common cause of lung cancer, it is estimated that 10–25% of all patients diagnosed with lung cancer are never smokers [2]. Never smokers with lung cancer are more likely to be women, have adenocarcinoma histology and are of East Asian ethnicity when compared to tobacco smokers with lung cancer [3–5] Apart from these now well-established epidemiological differences, recent research has uncovered several key molecular alterations that are more frequently detected in never smokers with lung cancer. Some of these molecular alterations – such as activating mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene and the EML4–ALK fusion – have therapeutic relevance in the treatment of patients with advanced-stage lung cancer [6–10]. Comprehensive genomic analysis by whole

genome sequencing has also identified significant differences between the tumour genome of lung cancer in never smokers (LCINS) and tobacco smokers with lung cancer [11] (Table 1). In this review we will discuss the genomic and epigenomic findings that characterise LCINS.

2.

Inherited susceptibility to LCINS

Despite the fact that tobacco smoking is the primary cause of lung cancer, identification of familial clustering of patients with lung cancer is suggestive of an inherited risk factor. Several studies have reported that patients with LCINS are more likely to have a family member diagnosed with lung cancer than a tobacco smoker with the same disease [12–15]. A systematic review of 11 studies identified that a positive family history of lung cancer increases the risk of developing lung cancer by 1.5-fold in never smokers [16]. A linkage study of 52 families with two or more members diagnosed with lung cancer identified the 6q23–25 region to be a major

* Corresponding author. Address: Division of Medical Oncology, Washington University School of Medicine, 660 S. Euclid, Box 8056, St. Louis, MO 63110, USA. Tel.: +1 314 362 5737; fax: +1 314 362 4232. E-mail address: [email protected] (R. Govindan). 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.004

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Table 1 – Characteristic molecular variations in lung cancer in never smokers (LCINS).

Genomic changes

Epigenomic changes

Markers

Lung cancer in tobacco smokers

LCINS

Point mutations in protein coding regions

Primarily G ! T transversions Common, 30–43% Rare, 0–7% Ratio = 1.5 14% 2–3% 15 pack years (9%) versus never smokers (51%); P < 0.005. In addition, EGFR TK mutations were not detected in tobacco smokers with more than 75 pack year exposure. The EGFR TK inhibitor erlotinib was initially approved for the treatment of all patients with advanced NSCLC in the second- and third-line settings. The discovery of activating EGFR TK mutations led to several randomised trials comparing EGFR TK inhibitors with chemotherapy in the front-line

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setting in patients with EGFR TK mutations [41–43]. Results from these trials have now established EGFR TK inhibitors as the standard front-line treatment for patients with advanced-stage NSCLC that is positive for EGFR TK mutation. Mutations involving the HER2 gene have been shown to be more frequent in never smokers with adenocarcinoma [9]. In a sample of 671 NSCLC tumours, the overall frequency of HER2 mutations was low at 1.6% (11/671), but they were more frequently identified in never or light smokers (8 of 248, 3.2%; P = 0.02). The HER2 mutations were not detected in tumours harbouring either the activating EGFR-TK or KRAS mutations. The STK11 gene encodes a serine–threonine kinase and plays an important role in cell proliferation and survival. Mutations involving the STK11 gene have been reported in 8% of all patients with lung cancer. In addition, they are more frequently present in tobacco smokers with lung cancer than in patients with LCINS (14% versus 3%; P = 0.007) [44]. EML4–ALK is a novel fusion gene present in approximately 5% of patients with NSCLC and is associated with an excellent therapeutic response to treatment with an Alk kinase inhibitor [10,45,46]. The fusion gene was more frequently identified in never smokers and younger patients with lung cancer. In addition, it appears to be mutually exclusive to EGFR TK and KRAS mutations. Two new transforming fusions involving the RET and ROS1 kinase genes at the 3 0 end have been identified in patients with lung cancer [47]. In one study, tumour samples from 936 patients with surgically resected NSCLC were tested for RET fusion genes by the reverse transcriptase polymerase chain reaction (PCR). The RET fusion was detected in 13 patients (1.4%), and these patients predominantly had adenocarcinoma histology (84.6%), were never smokers (82%) and many of them were younger: age 6 60 years at the time of diagnosis (73%) [48]. RET fusions have been shown to promote cell proliferation, and treatment with vandetanib, a multi kinase inhibitor with activity against RET kinase, was able to inhibit RET-induced cell proliferation [47]. Fusions involving the ROS1 gene in lung cancer were first reported in 2007 [49] and in a subsequent study, a fluorescent in situ hybridisation (FISH) based assay of 1000 NSCLC tumour samples identified ROS1 fusions in 18 (1.7%) samples [50]. Similar to patients with ALK or RET fusions, ROS fusions were found primarily in younger patients who were never smokers and had adenocarcinoma histology. Cell lines expressing ROS fusion were sensitive to treatment with the ALK inhibitor crizotinib. Overall, fusion genes involving the ALK, RET and ROS kinases are relatively rare molecular events in patients with NSCLC. These patients have similar clinico-pathological features, including that of being a never smoker. In addition, these fusions appear to be mutually exclusive to each other and to other known driver mutations in lung cancer, such as EGFR TK and KRAS mutations.

5.

Epigenetic alterations

Methylation of tumour suppressor genes – including p16INK4a, DAPK, RASSF1A, RARb, APC, CDH13, MGMT, hMLH1, hMSH2 and GSTP1 – leading to epigenetic silencing has been reported in lung cancer (reviewed in [51,52]). Studies have reported that

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methylation of the tumour suppressor gene p16 is less frequent in LCINS in comparison to lung cancer in tobacco smokers [53–57]. In a sample of 514 NSCLC tumours, which included 112 never smokers with adenocarcinoma, p16 (P = 0.007) and APC (P = 0.0007) methylation rates were significantly lower in never smokers than tobacco smokers with adenocarcinoma [54]. There was no significant difference in the methylation rate of the other tumour suppressor genes RASSF1A, RARb, CDH13, MGMT and GSTP1 between the two groups. The methylation index (total number of genes methylated/total number of genes examined) was significantly higher in tobacco smokers with lung cancer when compared to LCINS. In a follow-up study of 383 NSCLC tumours, the authors confirmed that the p16 methylation rate and the methylation index were significantly lower in LCINS (P < 0.0001) [55]. The methylation rate for APC was significantly lower (P < 0.0001) in never smokers when the analysis was restricted to adenocarcinoma. Subsequent studies have also reported a low p16 methylation rate in never smokers with adenocarcinoma [56,58]. There was no significant difference in the methylation rates of RASSF1A and DAPK between tobacco smokers with lung cancer and LCINS [56]. The loss of protein expression in protein mismatch repair genes hMLH1 and hMSH2 was reported to be more frequent in LCINS than in lung cancer in tobacco smokers [59]. In a sample of 77 resected NSCLC tumours, the loss of protein expression for hMLH1 (70% versus 46%) and hMSH2 (40% versus 10%) was more frequent in LCINS. The authors also reported that promoter methylation was the predominant mechanism for the loss of protein expression in both genes.

6.

Next-generation sequencing in LCINS

The advent of next-generation sequencing technologies now allows us unprecedented access to the tumour genome. Recently, next-generation sequencing of several tumour–normal pairs from patients with NSCLC was reported, and some of these patients were never smokers. Whole genome and transcriptome sequencing was performed in 17 patients with NSCLC, including five never smokers and 12 tobacco smokers [11]. The total number of mutations involving genes in protein coding regions was significantly higher in smokers than in never smokers; median 209 versus 18. In addition, the mutations in tobacco smokers were primarily G ! T transversions, whereas in LCINS they were G ! A transitions. For the first time this study identified that the G ! A transition point mutations in never smokers is a genome-wide phenomenon and is not restricted to KRAS and TP53 genes. Genomic and epigenomic profiling of tumour–normal pairs from six Korean patients with LCINS with exome seq, RNA seq, micro RNA seq and methylated DNA immunoprecipitation-sequencing (MeDIP-seq) confirmed the low mutation rate in LCINS [60]. They reported a total of 47 somatic mutations from the six LCINS tumour samples. In addition, they identified several novel fusion genes, including CCDC6– RET fusion which has been previously reported and could be a potential therapeutic target. Pathway analysis identified that genes involved in cell cycle regulation – particularly in

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Fig. 1 – Circos plots of tumour genome from a never smoker with lung cancer and a tobacco smoker with lung cancer. Adapted from Govindan et al [11].

G2/M transition – are very likely to have played a significant role in the development of these tumours.

7.

Conclusion

Cancer is a disease that is characterised by genomic and epigenomic alterations that result in malignant transformation of normal tissue. Such transforming genomic and epigenomic alterations are considered the drivers of the malignant disease and determine the clinical behaviour of the disease. In the case of lung cancer, tobacco-smoke exposure appears to be an important factor in determining the type of oncogenic drivers associated with the disease. This is well exemplified by findings from several studies showing that mutations involving TP53 and KRAS genes are more frequent in tobacco smokers with lung cancer, whereas LCINS is characterised by EGFR TK mutations, ALK, RET and ROS fusions. The differences between LCINS and lung cancer in tobacco smokers are not restricted to a few genes. Recent next-generation sequencing studies have found that the genome of LCINS is significantly different from the tumour genome of a tobacco smoker with lung cancer (Fig. 1). Overall, the number of mutations is significantly lower in LCINS, and the point mutations are primarily G ! A transitions. The higher number of genomic alterations seen in smokers with lung cancer is very likely due to the mutagenic field effect of tobacco-smoke exposure. The vast majority of these genomic alterations in tobacco smokers with lung cancer are believed to be passengers that do not have any role in the malignant transformation or progression. In contrast, in LCINS the absence of tobacco-smoke exposure and the relatively smaller number of identified genomic alterations suggest that most if not all of them play a role in its malignant transformation. Hence the LCINS genome may provide us with a relatively enriched and easily identifiable set of oncogenic drivers for lung cancer. In addition, the relatively small number of genomic alterations in LCINS also presents better opportunities for the development of targeted thera-

pies against LCINS. With the advances in sequencing technology and decreasing costs it is possible that, in the near future, advanced-stage LCINS may be primarily treated with molecularly targeted therapy, and it would be possible to achieve prolonged periods of disease control similar to the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST).

Conflict of interest statement The author is not a government employee. For the last 2 years, he has been a consultant for Pfizer, Roche Genentech, BristolMyers Squibb, Merck, Boehringer-Ingelheim, Abbott Oncology and Covidien.

R E F E R E N C E S

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[48] Wang R, Hu H, Pan Y, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol 2012;30:4352–9. [49] Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007;131:1190–203. [50] Bergethon K, Shaw AT, Ignatius Ou S-H, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863–70. [51] Digel W, Lubbert M. DNA methylation disturbances as novel therapeutic target in lung cancer: preclinical and clinical results. Crit Rev Oncol Hematol 2005;55:1–11. [52] Bowman RV, Yang IA, Semmler AB, Fong KM. Epigenetics of lung cancer. Respirology 2006;11:355–65. [53] Kim DH, Nelson HH, Wiencke JK, et al. P16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer. Cancer Res 2001;61:3419–24. [54] Toyooka S, Maruyama R, Toyooka KO, et al. Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer. Int J Cancer 2003;103:153–60.

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[55] Toyooka S, Suzuki M, Tsuda T, et al. Dose effect of smoking on aberrant methylation in non-small cell lung cancers. Int J Cancer 2004;110:462–4. [56] Divine KKPL, Marron-Terada PG, Liechty KC, et al. Multiplicity of abnormal promoter methylation in lung adenocarcinomas from smokers and never smokers. Int J Cancer 2005;114:400–5. [57] Liu Y, Lan Q, Siegfried JM, Luketich JD, Keohavong P. Aberrant promoter methylation of p16 and MGMT genes in lung tumors from smoking and never-smoking lung cancer patients. Neoplasia 2006;8:46–51. [58] Scesnaite A, Jarmalaite S, Mutanen P, et al. Similar DNA methylation pattern in lung tumours from smokers and never-smokers with second-hand tobacco smoke exposure. Mutagenesis 2012;27:423–9. [59] Wang Y-C, Lu Y-P, Tseng R-C, et al. Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples. J Clin Invest 2003;111:887–95. [60] Kim SC, Jung Y, Park J, et al. A high-dimensional, deepsequencing study of lung adenocarcinoma in female neversmokers. PLoS One 2013;8:e55596.

Bone metastases: Causes, consequences and therapeutic opportunities Jose Perez-Garcia, Eva Mun˜oz-Couselo, Javier Cortes

*

Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Medica Scientia Innovation Research (MedSIR), Barcelona, Spain

1.

Introduction

Although the skeleton is a common site of metastasis for many solid tumours, metastatic bone disease is particularly relevant in prostate and breast cancers. Thus, bone is the most frequent – and often the only – location of metastasis in patients with advanced prostate cancer. Moreover, up to 70% of patients with metastatic breast cancer develop bone metastases over the course of their disease. Metastatic bone involvement usually results in multiple skeletal complications leading to a significant deterioration in the quality of life for cancer patients. Pain, hypercalcemia and skeletal-related events (SREs) – such as the use of radiotherapy or surgery of bone, pathological fractures and spinal cord compression – are problems typically derived from bone metastases [1]. The pathogenesis of bone metastases is a complex process involving many interactions between tumour cells and osteoclasts and osteoblasts. Receptor activator of nuclear factor-jb (RANK) ligand (RANKL), which is expressed by osteoblasts and marrow stromal cells, is a potent inducer of osteoclast formation. In bone metastases, cytokines and growth factors secreted by tumour cells (interleukins 1 and 6, parathyroidhormone-related peptide, tumour necrosis factor, prostaglandin E2, and macrophage-colony-stimulating factor, amongst others) increase the expression of RANKL on marrow stromal cells and osteoblasts [2]. Following this, RANKL binds to its receptor, RANK, on the surface of osteoclast precursors and stimulates the differentiation of these cells to mature osteoclasts. This excessive RANKL-induced osteoclast activity results in increased bone resorption and local bone destruction, leading to the release of growth factors from the bone matrix that subsequently promotes tumour progression. This relationship between tumour and bone cells constitutes the vicious cycle of bone metastases. For all these reasons, patients with metastatic bone involvement who show higher levels of bone turnover mark-

ers have a particularly high risk for SREs in addition to worse clinical outcomes [3]. Treatment of bone metastases requires a broad strategy with different therapeutic options, including both local and systemic therapies. External-beam radiotherapy remains the mainstay of treatment for symptomatic bone metastases. However, considering that osteoclast-mediated bone resorption plays a critical role in the development of metastatic bone disease, its inhibition represents an attractive target for treating bone metastases. Below, some of the major management approaches are very briefly summarised.

2.

Bisphosphonates

Bisphosphonates are chemically stable derivatives of inorganic pyrophosphate. These compounds are potent inhibitors of osteoclast-mediated bone resorption through two well-recognised mechanisms of action. On the one hand, first-generation non-nitrogen-containing bisphosphonates (i.e. clodronate) are metabolised by osteoclasts to cytotoxic ATP analogues; on the other hand, second- and third-generation nitrogen-containing bisphosphonates, such as zoledronic acid and pamidronate, act by inhibiting farnesyl diphosphate synthase, a key enzyme of the mevalonate pathway. Over the last two decades these agents – in particular zoledronic acid and pamidronate – have been the most effective treatments in delaying or preventing SREs in patients with bone metastases from solid tumours, as well as in patients with multiple myeloma [4].

3.

Denosumab

Denosumab is a fully human monoclonal antibody that binds to RANKL in order to inhibit osteoclast activity. Denosumab has been evaluated in three identically designed, randomised, double-bind, phase III clinical trials [5–7]. Patients were

* Corresponding author. Tel.: +34 932746085. E-mail address: [email protected] (J. Cortes). 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.035

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Table 1 – Phase III studies with denosumab in patients with bone metastases or myeloma multiple. Number of patients

Type of tumour

Time to first on-study SRE

Overall survival

Time to disease progression

Refs.

1904

Prostate cancer

HR = 1.03 (P = 0.65)

HR = 1.06(P = 0.3)

[5]

1776

Myeloma multiple; solid tumours (except breast and prostate) Breast cancer

HR = 0.82 (P = 0.0002 for non-inferiority analysis; P = 0.008 for superiority analysis) HR = 0.84 (P = 0.0007 for non-inferiority analysis)

HR = 0.95 (P = 0.43)

HR = 1(P = 1)

[6]

HR = 0.82 (P < 0.001 for non-inferiority analysis; P = 0.01 for superiority analysis)

HR = 0.95 (P = 0.49)

HR = 1(P = 0.93)

[7]

2046

SRE, skeletal-related event; HR, hazard ratio.

randomly assigned to receive either subcutaneous denosumab 120 mg and intravenous placebo or intravenous zoledronic acid 4 mg and subcutaneous placebo every 4 weeks. The primary endpoint was time to first on-study SRE (defined as pathological fractures, the use of radiotherapy or surgery of bone, or spinal cord compression). These studies are summarised in Table 1. Overall, adverse events and serious adverse events were similar with both treatments, although more acute-phase reactions and renal adverse events occurred in the zoledronic acid group, whereas hypocalcemia was more frequent with denosumab. Additionally, the rate of osteonecrosis of the jaw was low in both arms (2%).

4.

Other agents

4.1.

Mammalian target of rapamycin (mTOR) inhibitors

mTOR inhibition decreases osteoclast maturation and increases osteoclast apoptosis, resulting in reduced bone resorption in animal models [8]. In the randomised phase III trial with everolimus in metastatic breast cancer (BOLERO-2), a total of 724 postmenopausal women with oestrogen-receptor-positive breast cancer refractory to non-steroidal aromatase inhibitor therapy were treated with exemestane and randomised (2:1) to everolimus or placebo. The addition of everolimus significantly improved median progression-free survival, the primary endpoint of this study (6.9 months versus 2.8 months; HR = 0.43; P < 0.001) [9]. An exploratory endpoint also included the evaluation of changes in bone turnover marker levels and the rate of progressive disease in bone, defined as unequivocal progression of a pre-existing bone lesion or the appearance of a new bone lesion [10]. Everolimus added to exemestane significantly decreased bone turnover marker levels at 6 and 12 weeks. Moreover, the cumulative incidence rate of progressive disease in bone was lower in the combination arm.

5.

Novel compounds

Other bone-targeting agents are currently under investigation, although the clinical development of SRC- and C-MET inhibitors is further along. Both have shown important

bone-specific activity in patients with breast or prostate cancer, as well as in preclinical models [11,12].

6.

Conclusions

A better understanding of the biology of bone metastases is establishing an exciting scenario in the treatment of this disease. This explosion of data has led to a large increase in knowledge and the subsequent introduction of new bone-targeted therapies in daily practice.

Conflict of interest statement Jose Perez-Garcia and Eva Mun˜oz-Couselo have no conflict of interest to declare. Javier Corte´s is a consultant for Novartis, Roche, Celgene and declares honoraria (speech) from Novartis, Roche, Celgene, Eisai.

R E F E R E N C E S

[1] Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350(16):1655–64. [2] Lipton A, Jun S. RANKL inhibition in the treatment of bone metastases. Curr Opin Support Palliat Care 2008;2(3):197–203. [3] Coleman RE, Major P, Lipton A, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 2005;23(22):4925–35. [4] Aapro M, Saad F, Costa L. Optimizing clinical benefits of bisphosphonates in cancer patients with bone metastases. Oncologist 2010;15(11):1147–58. [5] Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377(9768):813–22. [6] Henry DH, Costa L, Goldwasser F, et al. Randomized, doubleblind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29(9):1125–32. [7] Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, doubleblind study. J Clin Oncol 2010;28(35):5132–9.

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[8] Hussein O, Tiedemann K, Murshed M, et al. Rapamycin inhibits osteolysis and improves survival in a model of experimental bone metastases. Cancer Lett 2012;314(2):176–84. [9] Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366(6):520–9. [10] Gnant M, Baselga J, Rugo HS, et al. Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2. J Natl Cancer Inst 2012;105(9):654–63.

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[11] Saad F, Lipton A. SRC kinase inhibition: targeting bone metastases and tumor growth in prostate and breast cancer. Cancer Treat Rev 2010;36(2):177–84. [12] Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 2012;31(4):412–9.

Bone-targeted therapy in prostate cancer Fred Saad

*

University of Montreal Hospital Center, Montreal, Quebec, Canada

1.

Introduction

Androgen deprivation therapy (ADT) is standard for advanced prostate cancer and is now increasingly used as adjunct therapy in high-risk or locally advanced disease and for the treatment of recurring disease based on rising prostate-specific antigen levels. Testosterone stimulates bone formation directly by stimulating the osteoblast proliferation, inhibiting the apoptosis of both osteoblasts and osteoclasts, and indirectly by being a precursor of oestrogen which is also involved in inhibiting osteoclastic function (bone resorption). The effects of testosterone on preserving bone health are lost in the hypogonadal state induced by ADT [1]. The impact of ADT on bone loss and osteoporosis is well established through multiple studies. In one of these studies, non-metastatic prostate cancer cases were followed for 10 years; none of the patients on ADT had normal bone mass density (BMD) at the end of the study, and the prevalence of osteoporosis (T score < 2.5) was approximately 50% by 4 years and 80% by 10 years in men on ADT [2]. Bone metastases will occur in over 90% of men with lethal castration-resistant prostate cancer (CRPC). Due to the combined effect of bone fragility due to ADT and the presence of bone metastases, almost all patients will experience some form of morbidity related to bone metastases prior to succumbing from the disease. Complications go beyond pain and include pathological fracture, the need for palliative radiation or surgery, and spinal cord compression. These events impair quality of life and place a significant burden on health-care resources.

2.

Management options

2.1.

Life style modification and supplementation

Regular exercise, smoking cessation, lowering alcohol and caffeine intake, as well as oral vitamin D (800 IU daily) and calcium (500–1500 mg daily) supplementation are helpful in attenuating ADT-related bone loss, but they are insufficient to prevent or treat ADT-induced bone loss [3].

2.2.

Bone targeted therapy (anti-resorptive agents)

Bisphosphonates are the first and most widely used of the anti-resorptive agents. Due to their structural similarity to pyrophosphate, a normal component of bone matrix, they are integrated in the bone matrix by binding to hydroxyapatite crystals, resulting in inhibition of osteoclast-mediated bone resorption. Non-nitrogen-containing bisphosphonates are metabolized by osteoclasts to cytotoxic compounds, while nitrogen-containing bisphosphonates exert their effects on osteoclasts and tumour cells by inhibiting a key enzyme in the mevalonate pathway and by inducting osteoclast apoptosis. Nitrogen-containing bisphosphonates (e.g., pamidronate, zoledronic acid) are more potent than non-nitrogen-containing bisphosphonates (e.g., clodronate). Zoledronic acid is unique in that it contains two nitrogen groups, and it has been shown to be 40–850-fold more potent than other bisphosphonates [4]. In the setting of non-metastatic prostate cancer, bisphosphonates have consistently been found to reduce BMD loss associated with ADT in multiple randomized controlled trials, but none have had sufficient power or duration to demonstrate a reduction in fractures [5]. Zoledronic acid is the only bisphosphonate and the first osteoclast-targeted agent that has shown a protective effect against skeletal-related events (SRE) in patients with metastatic castration-resistant prostate cancer. The phase 3 study showed a 48% reduction in the mean annual incidence of SRE (P = 0.005), 5 months prolongation in the median time to first SRE (P = 0.009) and 36% reduction in the ongoing risk of SREs at 24 months [6,7]. Bisphosphonate-induced nephrotoxicity is a major concern, especially with intravenous bisphosphonates. Renal function monitoring and dose adjustment according to creatinine clearance are crucial to prevent significant deterioration in renal function. Other side effects include self-limiting flulike symptoms occurring with the first infusions, hypocalcaemia and osteonecrosis of the jaw (ONJ) [8]. The zoledronic acid bone metastases prevention study recently reported their results. The Zometa European Study [ZEUS] reported that there was no difference in the

* Corresponding author: Tel.: +1 514 890 8000x27466. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.038

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metastases rate after 4 years in high-risk non-metastatic prostate cancer. Of note, the incidence of new metastases was very low at approximately 13% [9]. Denosumab is a receptor activator of nuclear factor kappa B (RANK), a member of the tumour necrosis factor (TNF) receptor superfamily expressed by osteoclast precursors, and its ligand (RANKL) plays an essential role in regulating the osteoclast life cycle at different levels. Binding of the RANKL, secreted by osteoblasts and bone-marrow stromal cells, to its receptor RANK leads to differentiation, activation, and survival of osteoclasts which induce bone resorption [10]. Denosumab is a fully human monoclonal antibody that specifically targets RANKL, thus effectively inhibiting osteoclastic function and bone resorption, In a randomised placebo-controlled study in patients with non-metastatic prostate cancer receiving ADT, denosumab (60 mg subcutaneously every 6 months) was associated with significant improvements in BMD at the lumbar spine (6.7%), the total hip (4.8%) and distal one third of the radius (5.5%). Denosumab was also the first agent to show a reduction in the incidence of new vertebral fractures (1.5% versus 3.9%; P = 0.006) in patients on ADT [11]. In the setting of metastatic CRPC, denosumab (120 mg subcutaneously every 4 weeks) compared to zoledronic acid (4 mg intravenously every 4 weeks) significantly improved the time to first SRE (20.7 versus 17.1 months; P < 0.001 for non-inferiority; P = 0.008 for superiority). Overall survival and progression-free survival were similar for both drugs. Hypocalcaemia was more common with denosumab (13%) than with zoledronic acid (6%) (P < 0.0001) and a non-significant trend towards higher osteonecrosis of the jaw was seen with denosumab (2.3% versus 1.3%; P = 0.09) [12]. Calcium and vitamin D supplementation and monitoring of calcium levels while on therapy are essential to reduce the risk of hypocalcemia. In another placebo-controlled trial in non-metastatic CRPC, denosumab (120 q monthly) significantly increased the bone-metastasis-free survival in patients with non-metastatic CRPC by a median of 4.2 months (29.5 versus 25.2 months; HR, 0.85; 95%CI, 0.73–0.98; P = 0.028) [17]. Although hypocalcaemia was much lower in the setting of non-metastatic CRPC, the risk of ONJ was higher given the longer exposure time to denosumab [13].

2.3.

Osteonecrosis of the jaw (ONJ)

Osteonecrosis of the jaw is defined as exposed necrotic bone in the maxillofacial region that persists for more than 8 weeks. The incidence of ONJ in patients with CRPC receiving denosumab was similar to that in patients receiving zoledronic acid [12]. Although the aetiology is unclear, duration of therapy, poor dental hygiene, invasive dental surgery or ill-fitting dentures, concomitant corticosteroid use, radiotherapy and chemotherapy are identified risk factors. A conservative approach to the management of ONJ is recommended and includes oral rinses, antibiotics, pain control and minimal surface bony debridement to reduce sharp or rough bone surfaces. Biopsies are not recommended unless metastasis to the jaw is suspected. Good oral hygiene, baseline dental evaluation for high-risk individuals and avoidance of invasive

1 1 ( 20 1 3) 2 5 7–25 9

dental surgery during therapy reduce the risk of ONJ [14–16]. Most of the cases that were reported had had a tooth extraction or some other form of trauma that may have contributed to the development of ONJ. Most cases were treated conservatively, and less than 10% required bone resection. It is estimated that the risk is approximately 1–2% per year of exposure to bone-targeted therapies such as zoledronic acid and denosumab. Although bone-targeted therapy is beneficial, one must consider the risk of ONJ after 2 years of therapy when deciding whether to continue therapy.

2.4.

Radiopharmaceuticals – (radium-223)

In a recently completed phase III study of patients with metastatic CRPC, patients were randomized on a 2:1 basis to either radium-223 (an alpha-emitting bone seeker) or placebo. To be eligible for the study patients had to have bone metastases and to have progressed after chemotherapy or were not eligible to receive chemotherapy. Patients received either radium-223 or placebo every 4 weeks intravenously. Overall survival (OS) was the primary endpoint. Median survival was 14 months for the treated patients as opposed to 11.2 months for those who received a placebo, conferring approximately a 30% improvement in OS (HR = 0.699, P = 0.0022). The updated analysis involving 921 patients confirmed the radium223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P < 0.001). The study also showed a 5-month delay in time to skeletal-related events. This agent has recently been approved by the FDA and is the first bone-targeted agent to demonstrate a survival advantage.

3.

Conclusion

Patients with metastatic prostate cancer are at high risk for skeletal complications, including debilitating bone pain often requiring palliative radiation therapy, pathological fractures, and spinal cord compression. These complications impair quality of life and place a significant burden on health-care resources. They are due to the combined effects of bone metastases and ADT-related bone loss. The use of bone-targeted therapy (denosumab and zoledronic acid) has been shown to significantly delay and reduce the risk of these skeletal complications. Studies have also suggested that introduction of these therapies prior to PAIN or SREs may further improve efficacy. Denosumab (60 mg every 6 months) has recently been approved for prevention of bone loss related to ADT. Most recently the radiopharmaceutical, radium-223, was shown to delay skeletal complications and also to improve overall survival in patients ineligible for or having failed chemotherapy. The combination of early bone-targeted therapy followed by radium-223 later in the disease continuum appears to lead to further improvements in the management of bone metastases in CRPC.

Conflict of interest statement Consultant and research conducted with Amgen, Bayer, Novartis.

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R E F E R E N C E S

[1] Riggs BL, Khosla S, Melton 3rd LJ. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002;23:279–302. [2] Morote J, Morin JP, Orsola A, et al. Prevalence of osteoporosis during long-term androgen deprivation therapy in patients with prostate cancer. Urology 2007;69:500–4. [3] Brown JP, Josse RG. Scientific Advisory Council of the Osteoporosis Society of Canada. 2002 Clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 2002;167(Suppl. 10):S1–S34. [4] Green JR. Bisphosphonates: preclinical review. Oncologist 2004;9(Suppl. 4):3–13. [5] Egerdie B, Saad F. Bone health in the prostate cancer patient receiving androgen deprivation therapy: a review of present and future management options. CUAJ 2010;4:129–35. [6] Saad F, Gleason DM, Murray R, et al. A randomized, placebocontrolled trial of zoledronic acid in patients with hormonerefractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458–68. [7] Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879–82. [8] Conte P, Guarneri V. Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. Oncologist 2004;9(Suppl. 4):28–37.

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[9] Wirth M, Tammela T, Huland H, et al. Efficacy and safety of the Zometa European study Abstract EAU; March 2013. [10] Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337–42. [11] Smith MR, Egerdie B, Hernandez Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361:745–55. [12] Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377:813–22. [13] Smith MR, Saad F, Coleman R, et al. Denosumab and bonemetastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebocontrolled trial. Lancet 2012;379:39–46. [14] Hoff AO, Toth BB, Altundag K, et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008;23:826–36. [15] Ruggiero S, Gralow J, Marx RE, et al. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Practice 2006;2:7–14. [16] Saad F, Brown JE, Van Poznak C, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 2012;23:1341–7. [17] Parker C, Nilsson S, Heinrich D. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer NEJM 2013;369.

Current role of human papillomavirus in head and neck oncology Pernille Lassen

*

Aarhus University Hospital, Department of Experimental Clinical Oncology, Aarhus C, Denmark

Tobacco and alcohol were, until recently, considered to be the major risk factors in carcinogenesis of head and neck cancer (HNSCC). However, during the past decade a causal association between infection with human papillomavirus (HPV) and HNSCC has been established [1], and this ‘new’ aetiological factor has changed the conventional understanding of HNSCC because of the extensive influence of the virus on the epidemiology, clinical presentation and treatment outcome for patients with HNSCC. Association with HPV is predominantly a matter of concern in tumours of the oropharynx, especially in tonsillar cancer [2,3], and a dramatic increase in the incidence of oropharyngeal cancer (OPC) has been reported in several Western countries over the past 30 years [4–8]. Based on the observations that, simultaneously, there has been an increase in the frequency of HPV-positivity among OPCs [4,9], infection with HPV seems to be the dominant cause of this development. Moreover, in the same time period a decrease in tobacco-smoking seems to be responsible for a reduction in the incidence of HNSCC outside the oropharynx [6], at least in Western countries. The natural history of oral HPV infection remains to be fully elucidated, and although the exact mechanism is not known, oral–genital contact is assumed to be the primary mode by which HPV is transmitted to the oral mucosa, and several case–control studies have shown an association between HPV-related HNSCC and sexual behaviour (reviewed by Gillison et al. [3]). The optimal method for detecting HPV in tumours is controversial, and both in-situ hybridisation and the polymerase chain reaction (PCR) are commonly used; p16-immunohistochemistry has gained broad acceptance as a surrogate marker and is also widely used in the clinical setting [10,11]. HPV-related HNSCC constitutes a clinically distinct subgroup of cancers in terms of molecular biology, patient characteristics and sensitivity to treatment, and this on the whole differentiates it markedly from HPV-negative tumours. The molecular profile of HPV-related HNSCC is distinct, with P53 degradation, retinoblastoma RB pathway

inactivation and p16 up-regulation. By contrast, HPV-negative tumours are characterised by TP53 mutation and downregulation of p16 [12,13]. Patients with HPV-related HNSCC tend to be younger, have less comorbidity and a better performance status [14–16], and are less declined to be abusers of tobacco and alcohol [6,15] compared with HPV-negative patients. Tumour HPV status has a major impact on outcome for patients with HNSCC, and compared with HPV-negative patients, tumour-control and survival are highly significantly better for patients with HPV-positive tumours. This has been shown repeatedly in several clinical trials and with the use of a variety of different treatment schedules [17–22] and is believed to be caused in part by a higher sensitivity to radiotherapy of HPV-positive tumours, presumably because of the distinct molecular profile [23], combined with a better general health status in this group of patients. Smoking negatively affects survival in HNSCC, and the accumulated lifetime number of pack years independently impacts prognosis for both HPV-positive and -negative tumours [21,24]; implementation of smoking history in the risk stratification of HNSCC is under consideration. As a consequence of this profound impact of HPV in HNSCC, this ‘new’ type of cancer has attracted a lot of attention, and separate therapeutic treatment strategies based on tumour HPV status are in the pipeline. In light of the enhanced sensitivity to treatment of HPV-related HNSCC, de-intensification of present treatment strategies in order to avoid excessive toxicity has been proposed for selected patients with minimal risk of distant metastasis [25]. On the other hand, patients with HPV-negative tumours have a very poor prognosis, and efforts should be made to improve treatment efficacy and compliance in this group of patients.

Conflict of interest statement None declared.

* Tel.: +45 7846 2620; fax: +45 8619 7109. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.039

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R E F E R E N C E S

[1] Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709–20. [2] Sudhoff HH, Schwarze HP, Winder D, et al. Evidence for a causal association for HPV in head and neck cancers. Eur Arch Otorhinolaryngol 2011;268:1541–7. [3] Gillison ML, Alemany L, Snijders PJ, et al. Human papillomavirus and diseases of the upper airway: head and neck cancer and respiratory papillomatosis. Vaccine 2012;30(Suppl. 5):F34–54. [4] Lassen P. The role of human papillomavirus in head and neck cancer and the impact on radiotherapy outcome. Radiother Oncol 2010;95:371–80. [5] Blomberg M, Nielsen A, Munk C, et al. Trends in head and neck cancer incidence in Denmark, 1978–2007: focus on human papillomavirus associated sites. Int J Cancer 2011;129:733–41. [6] Chaturvedi AK, Engels EA, Anderson WF, et al. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 2008;26:612–9. [7] Hammarstedt L, Dahlstrand H, Lindquist D, et al. The incidence of tonsillar cancer in Sweden is increasing. Acta Otolaryngol 2007;127:988–92. [8] Marur S, D’Souza G, Westra WH, et al. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol 2010;11:781–9. [9] Hammarstedt L, Lindquist D, Dahlstrand H, et al. Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. Int J Cancer 2006;119:2620–3. [10] Venuti A, Paolini F. HPV detection methods in head and neck cancer. Head Neck Pathol 2012;6(Suppl. 1):S63–74. [11] El-Naggar AK, Westra WH. P16 expression as a surrogate marker for HPV-related oropharyngeal carcinoma: a guide for interpretative relevance and consistency. Head Neck 2012;34:459–61. [12] Braakhuis BJ, Snijders PJ, Keune WJ, et al. Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst 2004;96:998–1006. [13] Chung CH, Gillison ML. Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications. Clin Cancer Res 2009;15:6758–62.

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[14] Smith EM, Ritchie JM, Summersgill KF, et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer 2004;108:766–72. [15] Gillison ML, D’Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 2008;100:407–20. [16] Worden FP, Kumar B, Lee JS, et al. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol 2008;26:3138–46. [17] Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. Effect of HPVassociated p16(INK4A) expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 2009;27:1992–8. [18] Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100:261–9. [19] Licitra L, Perrone F, Bossi P, et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 2006;24:5630–6. [20] Kumar B, Cordell KG, Lee JS, et al. EGFR, p16, HPV titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol 2008;26:3128–37. [21] Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24–35. [22] Kies MS, Holsinger FC, Lee JJ, et al. Induction chemotherapy and cetuximab for locally advanced squamous cell carcinoma of the head and neck: results from a phase II prospective trial. J Clin Oncol 2010;28:8–14. [23] Rieckmann T, Tribius S, Grob TJ, et al. HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiother Oncol 2013. http://dx.doi.org/10.1016/ j.radonc.2013.03.013 [Epub ahead of print]. [24] Gillison ML, Zhang Q, Jordan R, et al. Tobacco smoking and increased risk of death and progression for patients with p16positive and p16-negative oropharyngeal cancer. J Clin Oncol 2012;30:2102–11. [25] O’Sullivan B, Huang SH, Siu LL, et al. Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol 2013;31:543–50.

Novel therapeutic targets in diffuse large B-cell lymphoma Georg Lenz

*

Charite´ – Universita¨tsmedizin Berlin, Department of Hematology, Oncology and Tumor Immunology, Berlin, Germany

Diffuse large B-cell lymphoma (DLBCL) represents the most frequent lymphoma subtype and is considered a heterogeneous diagnostic category [1]. Using gene expression profiling, two major molecular subtypes termed germinal centre B-cell-like (GCB) DLBCL and activated B-cell-like (ABC) DLBCL can be distinguished [2]. Their gene expression profiles suggest that they arise from B-cells at different stages of differentiation. The GCB DLBCLs appear to originate from germinal centre B-cells, whereas the ABC DLBCLs may arise from post-germinal-centre B-cells that are in transition to being differentiated into plasma cells. Intriguingly, these two subtypes differ not only with respect to the expression of thousands of genes, but also utilise different oncogenic pathways and have significantly different survival rates following therapy [3,4]. ABC DLBCLs are characterised by inferior survival compared with GCB DLBCL patients when treated with a combined approach of the anti-CD20 antibody rituximab and CHOP chemotherapy [5]. Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved.

Recent advances in the understanding of the biology of these entities lead to the identification of a variety of potentially novel therapeutic targets for the treatment of affected patients. ABC DLBCLs are characterised by constitutive activation of the oncogenic nuclear factor-jB (NF-jB) pathway, which promotes cell proliferation and differentiation and suppresses apoptosis [6]. NF-jB signaling is mediated by a family of transcription factors that are normally kept inactive in the cytoplasm by binding to inhibitory IjB proteins. The constitutive activation of NF-jB in ABC DLBCL is caused in the vast majority of cases by somatically acquired mutations that affect positive (CARD11, CD79B and MYD88) and negative (TNFAIP3) NF-jB regulators [7–10]. Inhibition of NF-jB was toxic to preclinical models of ABC DLBCL [6]. Therefore, targeting the NF-jB pathway seems to be an attractive therapeutic approach. Such a strategy was taken by Dunleavy and colleagues in a recent phase II study in which the efficacy of bortezomib was investigated in DLBCL [11]. Preclinical data suggest that bortezomib inhibits NF-jB by blocking IjBj degradation. The efficacy of bortezomib in combination with chemotherapy was evaluated in relapsed/refractory ABC and GCB DLBCL patients [11]. Interestingly, the response rates were significantly higher in ABC compared with GCB DLBCL, and even more importantly, patients with ABC DLBCL had a significantly superior overall survival. These results poten-

tially suggest that inhibition of NF-jB might be a promising approach in ABC DLBCL. This hypothesis was further supported by recently presented data on the efficacy of the Bruton agammaglobulinemia tyrosine kinase (BTK) inhibitor ibrutinib [12]. BTK plays an important role in activating NFjB following B-cell receptor stimulation. Using this inhibitor, impressive response rates in relapsed and refractory ABC DLBCL could be achieved. Collectively, these data indicate that inhibition of the oncogenic NF-jB pathway might be a future option to overcome the adverse prognosis of patients affected by ABC DLBCL. While patients with GCB DLBCL are characterised by superior prognosis compared with ABC DLBCL [5], a substantial proportion of GCB DLBCL patients are not cured by standard treatment. GCB DLBCLs frequently express the transcriptional repressor BCL-6 that plays an important role in the germinal centre reaction. BCL-6 therefore might represent a novel target for GCB DLBCLs. In preclinical models, specific BCL-6 inhibitors showed impressive efficacy [13,14]. GCB DLBCLs are furthermore frequently characterised by deregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway [4]. The PI3K signaling cascade is initiated with the phosphorylation of phophatidylinositol 4,5-bisphosphate (PIP2) to phophatidylinositol 3,4,5-trisphosphate (PIP3), resulting in cellular processes such as proliferation, cell survival and cell

* Tel.: +49 30 450 559203; fax: +49 30 450 559975. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.041

EJC SUPPLEMENTS

growth. Various PI3K inhibitors are currently being evaluated in different cancer types and might represent a promising therapeutic approach in GCB DLBCL. In summary, ABC and GCB DLBCL represent molecular subtypes that are dependent on different oncogenic signaling pathways. In clinical reality this biological diversity is still insufficiently taken into account. Efforts to distinguish these entities using gene expression profiling or next-generation sequencing will pave the way to more specific and less toxic treatment strategies.

Conflict of interest statement G.L. received funding and honoraria from Novartis.

Funding sources This work was funded by research grants to G.L. from the Deutsche Krebshilfe, the German Research Foundation and the Else Kro¨ner-Fresenius-Stiftung.

R E F E R E N C E S

[1] Nogai H, Dorken B, Lenz G. Pathogenesis of Non-Hodgkin’s lymphoma. J Clin Oncol 2011;29:1803–11. [2] Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000;403:503–11. [3] Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002;346:1937–47.

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[4] Lenz G, Wright GW, Emre NC, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A 2008;105:13520–5. [5] Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008;359:2313–23. [6] Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity Is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 2001;194:1861–74. [7] Lenz G, Davis RE, Ngo VN, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 2008;319:1676–9. [8] Compagno M, Lim WK, Grunn A, et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 2009;459:717–21. [9] Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cellreceptor signalling in diffuse large B-cell lymphoma. Nature 2010;463:88–92. [10] Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011;470:115–9. [11] Dunleavy K, Pittaluga S, Czuczman MS, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 2009;113:6069–76. [12] Wilson W, Gerecitano J, Goy A, et al. The Bruton’s tyrosine kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. Blood 2012 [ASH Abstract 623]. [13] Cerchietti LC, Yang SN, Shaknovich R, et al. A peptomimetic inhibitor of BCL6 with potent anti-lymphoma effects in vitro and in vivo. Blood 2009;113:3397–405. [14] Cerchietti LC, Ghetu AF, Zhu X, et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell 2010;17:400–11.

Novel teatment options in early-stage non-small-cell lung cancer Jan P. van Meerbeeck

*

Oncology /MOCA, Antwerp University Hospital, Edegem, Belgium

1.

Introduction

Early-stage lung cancer refers to patients presenting with clinical stages I and II non-small-cell lung cancer (NSCLC) according to the TNM classification. They represent approximately 20–25% of incident cancer cases in most populationbased cancer registries, and radical surgical resection is considered the treatment of choice in operable and fit patients [1]. Although no prospective, randomised trial exists to compare surgery versus radiotherapy in the treatment of early-stage NSCLC, surgical resection has traditionally been considered the treatment of choice. Markedly improved survival rates are reported in surgical series in comparison to patients who did not undergo surgical resection for a variety of reasons [2]. This abstract will address some of the challenges of novel treatment options in these patients. With low-dose computed tomography (CT) scan screening becoming the new standard of early detection of lung cancer, physicians and surgeons will be confronted with an increase in T1a lung cancer, disguised as non-calcified nodules. Although it is tempting to proceed to a parenchyma-sparing resection for issues of functional operability, the risk of local recurrence and inadequate intraoperative lymph-node staging should not be neglected. Whether some of these lesions can be treated by so-called sublobar resection – consisting of either anatomical segmentectomy or wedge excision – is currently the subject of intensive investigation by appropriate randomised trials. For a limited resection to be oncologically valid, a precise pre- and intraoperative diagnosis is imperative. In terms of preoperative diagnosis, specific criteria on chest CT as percentage ground-glass opacity (GGO), tumour shadow disappearance rate and histogram analysis have been shown to have a high predictive value[3]. Three similar trials – JCOG 0802 in Japan, CALGB 140503 in North America and IEO S638/311 in Italy – are currently enroling patients, and collaboration is highly regarded [4,5]. More tailored, personalised surgical therapy has recently been introduced. Quality-of-life parameters and surgical quality indicators become increasingly important to deter-

mine the short-term and long-term impact of a surgical procedure. International databases currently collect extensive surgical data, allowing more precise calculation of mortality and morbidity according to predefined risk factors. Centralisation of care has been shown to improve results [6]. Functionally inoperable patients are nowadays proposed stereotactic ablative body radiotherapy (SABR), in which hypofractionated doses are administered over a short period of time [7,8]. Although lung-cancer-specific time-to-event outcome data seem very promising, unusual late toxicity is increasingly being reported, and there is concern regarding the inclusion of variable fractions of non-pathologically proven non-calcified nodules [9]. Clearly, before extrapolating these results to functionally operable patients, large randomised trials with an unequivocal non-inferiority design should be carried out [10]. Other radiotherapeutic techniques in development to improve local control with minimal pulmonary toxicity are the application of different breath control devices and the introduction of hadron/proton therapy. Radiofrequency ablation is another way of tackling pulmonary masses and nodules whereby a transthoracic radioprobe is inserted under CT guidance, allowing for a subsequent ‘cooking’ with electromagnetic energy. The technique is well known in the treatment of primary liver cancer and metastases, and several uncontrolled series have been reported in a mixed series of patients with primary lung cancer and lung metastases [11]. However, the technique lacks standardisation and long-term results, but is promising for centres which cannot afford SABR. There are currently no ongoing randomised trials [12]. An endobronchial application is certainly promising. Adjuvant chemotherapy is the present standard of care in completely resected stages pII and III NSCLC, albeit toxicity is considerable and the observed improvement in outcome modest. Patient selection using molecular and biological biomarkers and signatures is likely to increase the fraction of patients benefiting from it. The large BIO-IALT study has described a number of prognostic and predictive factors, although recent reports challenge the accuracy of the

* Corresponding author: Tel.: +32 3 821 34 12. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.037

EJC SUPPLEMENTS

techniques used [13,14]. One of the most critical issues regarding tumour biomarkers concerns methodology. Techniques for carrying out the test, the reagents used, methods used to score/quantify the results, the analysis and interpretation of the results are all critical yet prone to variability and error. Some are more subjective than others; many are simple and readily available, others are complex, expensive and less accessible. Complexity does not guarantee accuracy, greater reliability or relevance. In terms of biomarker testing of tumour samples, the handling and processing of the tissues prior to testing is of critical importance yet difficult to standardise, but these factors are often ignored or overlooked [15]. Biomarkers might be selected for patients preferably treated with agents targeted at hallmark pathways of oncogenesis: e.g. sustained proliferation, angiogenesis and avoiding immune destruction. Trials investigating the efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, vascular endothelial growth factor (VEGF) inhibitors or vaccines against melanoma antigen (MAGE) are currently ongoing, and their results are expected to alter clinical practice [16,17]. Although neoadjuvant chemotherapy is better tolerated and its added value to outcome is similar to that of adjuvant, its widespread use suffers from a low rate of pathological remission, which is a precondition for a lesser resection to be carried out. Window-of-opportunity trials with neoadjuvant targeted agents and biological imaging are promising [18]. They have so far not been conducted in a biomarker-selected population. The role of postoperative radiotherapy is currently limited to non-radically resected cases, although there are uncontrolled observations of its efficacy in subgroups of completely resected patients. In the ongoing randomised LUNGART trial, its role is explored in patients with clinical or pathological N2 disease [19]. An important handicap in present-day patient selection is the inaccuracy of clinical staging. Half or more of clinically staged patients are up- or down-staged at surgery [20]. Positron emission tomography–CT (PET–CT) scan and minimally invasive mediastinal ultrasound techniques are expected to improve on this figure and result in a stage shift.

Conflict of interest statement None declared.

R E F E R E N C E S

[1] Crino` L, Weder W, van Meerbeeck J, Felip E. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21(Suppl. 5):103–15. [2] Reif MS, Socinski MA, Rivera MP. Evidence-based medicine in the treatment of non-small-cell lung cancer. Clin Chest Med 2000;21:107–20. ix. [3] Ikeda K, Awai K, Mori T, et al. Differential diagnosis of ground-glass opacity nodules: CT number analysis by threedimensional computerized quantification. Chest 2007;132:984–90.

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[4] Van Schil PE, Asamura H, Rusch VW, et al. Surgical implications of the new IASLC/ATS /ERS adenocarcinoma classification. Eur Respir J 2012;39:478–86. [5] Anonymous. Comparison of different types of surgery in treating patients with stage IA non-small cell lung cancer. http://www.clinicaltrials.gov/ct2/show/NCT00499330 [accessed 22.05.13]. [6] von Meyenfeldt EM, Gooiker GA, van Gijn W, et al. The relationship between volume or surgeon specialty and outcome in the surgical treatment of lung cancer: a systematic review and meta-analysis. J Thorac Oncol 2012;7:1170–8. [7] Palma D, Lagerwaard F, Rodrigues G, Haasbeek C, Senan S. Curative treatment of Stage I non-small-cell lung cancer in patients with severe COPD: stereotactic radiotherapy outcomes and systematic review. Int J Radiat Oncol Biol Phys 2012;82:1149–56. [8] De Ruysscher D, Faivre-Finn C, Nestle U, et al. European Organisation for Research and Treatment of Cancer recommendations for planning and delivery of high-dose, high-precision radiotherapy for lung cancer. J Clin Oncol 2010;28:5301–10. [9] Ball D. Extracranial stereotactic body radiotherapy for stage I non-small cell lung cancer: still investigational or standard of care? J Thorac Oncol 2008;3:1209–10. [10] Anonymous. Surgery with or without internal radiation therapy compared with stereotactic body radiation therapy in treating patients with high-risk stage I non-small cell lung cancer. Available from: http://www.clinicaltrials.gov/ct2/ show/NCT01336894 [accessed 22.05.13]. [11] de Bae`re T, Palussie`re J, Aupe´rin A, et al. Midterm local efficacy and survival after radiofrequency ablation of lung tumors with minimum follow-up of 1 year: prospective evaluation. Radiology 2006;240:587–96. [12] Bilal H, Mahmood S, Rajashanker B, Shah R. Is radiofrequency ablation more effective than stereotactic ablative radiotherapy in patients with early stage medically inoperable non-small cell lung cancer? Interact Cardiovasc Thorac Surg 2012;15:258–65. [13] Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006;355:983–91. [14] Friboulet L, Olaussen KA, Pignon JP, et al. ERCC1 isoform expression and DNA repair in non-small-cell lung cancer. N Engl J Med 2013;368:1101–10. [15] Kerr KM. Personalized medicine for lung cancer: new challenges for pathology. Histopathology 2012;60:531–46. [16] Anonymous. Chemotherapy With or without bevacizumab in treating patients with stage IB, stage II, or stage IIIA nonsmall lung cancer that was removed by surgery. Available from: http://clinicaltrials.gov/ct2/show/NCT00324805 [accessed 22.05.13]. [17] Anonymous. GSK1572932A antigen-specific cancer immunotherapeutic as adjuvant therapy in patients with non-small cell lung cancer. Available from: http:// clinicaltrials.gov/ct2/show/NCT00480025 [accessed 22.05.13]. [18] Schaake EE, Kappers I, Codrington HE, et al. Tumor response and toxicity of neoadjuvant erlotinib in patients with earlystage non-small-cell lung cancer. J Clin Oncol 2012;30: 2731–8. [19] Anonymous. Radiation therapy in treating patients with nonsmall cell lung cancer that has been completely removed by surgery. Available from: http://clinicaltrials.gov/ct2/show/ NCT00410683 [accessed 22.05.13]. [20] Van Meerbeeck JP, Nicholson M, Gilligan D, et al. Adjuvant or neoadjuvant chemotherapy in early-stage non-small cell lung cancer (NSCLC): how would staging affect the patients treated? J Clin Oncol 2008(26 Suppl.) [abstract 7509].

Oncoplastic surgery – Standard of care Andrew D. Baildam

*

Breast & Oncoplastic Surgery, The Barts Breast Centre, St. Bartholomew’s Hospital, West Smithfield, London, UK

1. Introduction Over the last decade the whole approach to breast cancer surgery has changed radically from its ‘general surgery’ roots. There are few surgical specialties that have changed so much. The initial phase was the attention to wide local excision surgery, employing a more sensitive take on breast conservation, with scar placement and parenchymal reshaping. Then the concept of avoiding mastectomy by means of more extensive wide tumour excision together with partial breast reconstruction led to a flurry of innovations involving volume replacement and displacement techniques [1]. Oncoplastic breast surgery as a specialty now encompasses all elements of breast cancer surgery: appropriate cancer resection, skinsparing mastectomy and immediate breast reconstruction, the full elements of total and partial breast reconstruction and adjustment for breast asymmetry by augmentation, reduction mammaplasty or mastopexy for the contralateral unaffected breast [2]. The legacy of historical surgical training has meant that until recently few surgeons have been equipped to offer this cancer surgery/cosmetic/reconstructive breast surgery hybrid approach. This is changing with training initiatives. Over the last decade approximately 90 surgeons in the United Kingdom have undergone 1-year-long senior fellowships in oncoplastic breast surgery in nine tertiary centres, trained by both breast and plastic surgeons seamlessly. This approach is changing the quality of surgical care for the benefit of women. It has also led to a rejuvenation of breast surgery away from purely resection-based operations that had remained unchanged for many decades, to an innovative specialty with creative concepts and aesthetic detail. In turn, the result in the UK has been marked interest amongst trainee surgeons to enter breast surgery as a career, and applications for the national fellowships are highly competitive. Nevertheless much breast cancer surgery is still delivered by general surgeons, so care for individual women may involve surgeons from general as well as plastic/reconstructive

surgery backgrounds now working together in an ‘oncoplastic multidisciplinary team’. In 2007 extensive guidelines were developed in the UK to address inequalities in surgical provision. Oncoplastic Breast Surgery – a guide to good practice was a joint venture between the Association of Breast Surgery at BASO, the British Association of Plastic, Reconstructive and Aesthetic Surgery (BAPRAS), and the Breast Surgery Interface Training Committee at The Royal College of Surgeons of England [3]. This was intended to be for women with breast cancer, and all those involved in their care, to ensure the highest standards in setting up and delivering an oncoplastic breast service. In 2012 the guidelines were revised and newly published, and constitute a fully comprehensive document describing high standards of care for all aspects of oncoplastic and reconstructive breast surgery. They also cover aspects of the processes, the patient’s journey and arrangements for both equipment needs and team participants. The advantage of the revision is that the 5 years’ experience in developing models of care has been incorporated by the multispecialty team of writers into the 2012 document. The UK document is unique in its ambition to raise surgical quality nationally, to ensure that patients are aware of what is available, and to inform surgeons, allied professionals and hospital administrators about what is required to provide a modern highquality standard of care for women with breast cancer. These guidelines can be accessed online through either the Association of Breast Surgery or BAPRAS websites: ‘Oncoplastic breast reconstruction – Guidelines for Best Practice, 2012, Eds Dick Rainsbury and Alexis Willet’ (http://www.associationofbreastsurgery.org.uk/media/23851/final_oncoplastic_ guidelines_for_use.pdf). The role of surgery in the management of women with breast cancer remains all important and fundamental. Its role in the prevention of breast cancer for women at high risk by virtue of family history or gene mutation is increasing.

* Tel.: +44 161 491 2153. E-mail addresses: [email protected], [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.042

EJC SUPPLEMENTS

Conflict of interest statement None declared.

R E F E R E N C E S

[1] Audretsch WP. Reconstruction of the partial mastectomy defect: classification and method. In: Spear SL, editor. Surgery

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of the breast: principles and art. Philadelphia: Lippincote Raven Publishers; 1998. p. 155–96. [2] Baildam AD. Oncoplastic surgery of the breast. Br J Surg 2002;89:532–3. [3] Association of Breast Surgery at BASO. BAPRAS, and the Training Interface Group in Breast Surgery. Oncoplastic breast surgery – a guide to good practice. Eur J Surg Oncol 2007;33:S1–23.

Role of aggressive surgery for peritoneal metastases Dominique Elias *, Fre´de´ric Dumont, Charles Honore´, Diane Goe´re´ Gustave Roussy, Cancer Campus, Grand Paris, France

1. Peritoneal metastasis

cavity:

a

particular

site

of

The spatial conformation and the poor prognosis of peritoneal metastases (PM) make it an original entity. Once contaminated by tumour cells, disease spread is rapid and multidirectional over a surface that is equal to the body surface area in m2. The prognosis of PM is poorer than that of metastatic spread elsewhere; patients with colorectal metastases treated with chemotherapy and targeted therapies have a median survival of 15 months with PM versus 21 months without PM (P < 0.001) [1]. The presence of PM is thus traditionally deemed a fatal event. Complete cytoreductive surgery (CCRS) resects all visible peritoneal deposits, and the remaining invisible disease is subsequently treated with a high local concentration of chemotherapy potentiated by hyperthermia (HIPEC) in one session. This aggressive surgery can therefore be proposed only for disease confined to the peritoneum. According to the origin of the disease, such treatment is administered in two out of three colorectal carcinomas, one out of three gastric carcinomas, seven out of ten ovarian carcinomas, nine out of ten pseudomyxomas and eight out of ten mesotheliomas.

2. Aggressive surgery as a state of the art: pseudomyxoma and mesothelioma CCRS + HIPEC is considered the gold standard treatment for these two peritoneal malignancies. In a retrospective multicentric registry, including 2298 patients with pseudomyxoma from 16 specialised units using this combined approach [2], median survival was 16.3 years and 10-year survival was 63%. Mortality was 2%, and major complications occurred in 24%. The main prognostic factors in the multivariate analysis were the histological subtype, a high extent score and no HIPEC. CCRS achieved the best outcome. Similar conclusions were drawn for malignant mesothelioma in a multi-institutional registry including 405 patients [3] in which only 46% underwent CCRS. Median survival was 53 months and 5-year survival was 47%.

3. Aggressive surgery as a new therapeutic approach: colorectal carcinoma 3.1.

Long-term results after CCRS plus HIPEC

Ten years ago the results of a randomised study [4] – which included 105 patients treated for colorectal PM (systemic chemotherapy versus with surgery plus HIPEC) – demonstrated significantly prolonged survival in patients treated with surgery plus HIPEC, with a median survival twofold higher (P = 0.03), although CCRS was achieved in only 38% of cases. This was confirmed in another study [5] comparing two similar groups in terms of the main patient characteristics. All patients underwent a laparotomy and had resectable PM; 48 patients were treated with CCRS + HIPEC in one centre, and 48 were treated in five other centres without HIPEC. After a minimal follow-up of 63 months, 5-year overall survival was 51% in the CCRS + HIPEC group and 13% for patients in the no-HIPEC group (P < 0.05). Long-term results of primary CCRS + HIPEC demonstrated that definitive cure of PM was possible in 16% of the 93 patients treated between 1995 and 2004 [6], a rate which is close to that obtained with a similar long follow-up after hepatectomy for liver metastases (LM). Median survival was 36 months at that time, but attained 48 months in 2011 [7], emphasising a learning-curve effect and better patient selection. CCRS + HIPEC is wrongly reputed to cause excessive morbidity, but in specialised centres and in selected patients mortality is lower than 5% and grade 3–4 morbidity is lower than 30%. Aggressive surgery plus HIPEC is also considered costly, but its clear superiority over the usual palliative therapies in terms of QALY (cost-efficacy) has been demonstrated. Regarding prognostic factors, the results of the French Registry – which analysed 523 patients treated with CCRS + HIPEC – showed that the extent of PM (scored with the peritoneal cancer index, PCI) is the main prognostic factor [8]. There were no survivors when the PCI exceeded 20, and we now consider a PCI above 20 to be a contraindication.

* Corresponding author: Address: Gustave Roussy, 114 Rue Edouard Vaillant, 94807 Villejuif, France. Tel.: +33 1 42 11 40 85. E-mail address: [email protected] (D. Elias). 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.036

EJC SUPPLEMENTS

3.2.

Role of complete cytoreductive surgery alone

No randomised study has compared CCRS to systemic chemotherapy. The results of four retrospective series provide some elements of response: median survival was 28 months, with 5-year survival at 24%, showing clear but limited superiority over systemic chemotherapy alone. In contrast, an incomplete resection (R2) afforded no advantage, with survival rates similar to those reported with chemotherapy alone [8]. In conclusion, CCRS benefits patients with limited PM and a good general status.

3.3.

Role of hyperthermic intraperitoneal chemotherapy

No randomised study has been published to date. We are awaiting the results of Prodige 7, the French randomised trial comparing the survival of patients treated with CCRS + HIPEC to that of patients treated with CCRS alone, whose accrual was recently completed (n = 260). This study will define the real impact of HIPEC.

3.4.

Future

As this aggressive surgery gives far better results for limited PM, it should be used mainly to treat patients at a very early stage, but early diagnosis of PM cannot be done by clinical or imaging examinations. Only systematic second-look surgery (SLS) can detect PM early, but this aggressive approach should be proposed exclusively in patients at high risk of PM. In such patients (limited PM resected with the primary, a history of ovarian metastases and a perforated primary tumour) with no preoperative evidence of PM, SLS has allowed us to find macroscopic PM in 55% of cases [9], and to treat PM earlier with CCRS + HIPEC. A randomised multicentric trial (Prophylochip) comparing the standard treatment (follow-up) in these high-risk patients to the new one (secondlook + HIPEC) is ongoing.

4.

CCRS + HIPEC to treat PM of other origins

Indications are in progress for ovarian-, gastric-, NET- and rare disease-derived PM. The initial results of CCRS + HIPEC were disappointing, but progress in techniques and in indications in ongoing prospective trials is giving promising results.

5.

Conclusion

CCRS + HIPEC yields long-term survival in patients with PM. No clear and widely accepted definition of resectable PM exists. However, we postulate that when the patient has a good

1 1 ( 2 0 1 3 ) 2 6 8 –2 6 9

269

general status and when the extent of PM is limited, without extraperitoneal disease, this approach is beneficial.

Conflict of interest statement None declared.

R E F E R E N C E S

[1] Klaver YL, Simkens LH, Lemmens VE, Koopman M, Teerenstra S, Bleichrodt RP, et al. Outcomes of colorectal cancer patients with peritoneal carcinomatosis treated with chemotherapy with and without targeted therapy. Eur J Surg Oncol 2012;38:617–23. [2] Chua T, Moran B, Sugarbaker P, Levine E, Glehen O, Gilly F, et al. Early and long-term outcome data on 2298 patients with pseudomyxoma peritonei of appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol 2012;30:2449–56. [3] Yan TD, Deraco M, Baratti D, Kusamara S, Elias D, Glehen O, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multiinstitutional experience. J Clin Oncol 2009;27:6237–42. [4] Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003;21:3737–43. [5] Elias D, Lefevre JH, Chevalier J, Brouquet A, Marchal F, Classe JM, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol 2009;27:681–5. [6] Goe´re´ D, Malka D, Tzanis D, Gava V, Boige V, Eveno C, et al. Is there a possibility of cure in patients with colorectal peritoneal carcinomatosis amenable to complete cytoreductive surgery and intraperitoneal chemotherapy? Annals of Surgery 2013;257:1065–71. [7] Quenet F, Goe´re´ D, Mehta SS, Roca L, Dumont F, Hessissen M, et al. Results of two bi-institutional prospective studies using intraperitoneal oxaliplatin with or without irinotecan during HIPEC after cytoreductive surgery for colorectal carcinomatosis. Ann Surg 2011;254:294–301. [8] Elias D, Gilly F, Boutitie F, Quenet F, Bereder JM, Mansvelt B, et al. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin Oncol 2010;28:63–8. [9] Elias D, Honore´ C, Dumont F, Ducreux M, Boige V, Malka D, et al. Results of a systematic second-look surgery plus HIPEC in asymptomatic patients presenting a high risk of developing colorectal peritoneal carcinomatosis. Ann Surg 2011;254:289–93.

Successful clinical translation of preclinical combinations of radiation and immunotherapy Silvia C. Formenti *, Sandra Demaria New York University School of Medicine, New York University Cancer Institute, USA

1.

Introduction

Ionising radiation (IR) can induce immunogenic cell death in tumours, an effect likely to contribute to the success associated with radiotherapy (RT) for cancer. Recent studies suggest that radiotherapy can be applied as a powerful adjuvant to immunotherapy, and can even contribute to converting the irradiated tumour into an in situ vaccine, resulting in specific immunity against metastases [1]. Importantly, preclinical models of syngeneic tumours have reliably predicted clinical success in several distinct tumour settings and with several different immunotherapy/ radiation combinations. As a proof-of-principle trial, we have translated the preclinical evidence of a successful combination with Flt3 ligand and RT to a protocol of granulocyte– monocyte colony-stimulating factor (GM-CSF) and IR, and demonstrated out-of-field objective responses in 27% of patients with multiple metastases of solid tumours, defined as an abscopal effect [2] In-parallel mechanistic studies in the laboratory were conducted in the syngeneic mouse models of metastatic breast cancer. Results showed that radiation was synergistic with anti-CTLA-4 treatment, a strategy to break immune tolerance to the tumor. Multiple mechanisms contributed to thus synergy, including the RT-induced upregulation of a chemokine that promoted homing of effector T cells to the tumor. Intravital microscopy demonstrated that while both IR and CTLA-4 blockade given as monotherapy enhanced the motility of activated CD8 T cells infiltrating 4T1 tumours, IR with anti-CTLA-4 increased the arrest of T cells in contact with tumour cells, promoting the formation of an immune synapse between cytotoxic T cells and their targets. The latter required interaction between NKG2D on CD8+ T cells and its ligand, retinoic acid early inducible-1 (Rae-1), on the tumour cells, which was up-regulated by IR. Blocking NKG2D–Rae-1 interactions markedly increased the motility of anti-CTLA-4 treated T cells within irradiated tumours, inhibiting their contact with tumour cells and also abrogated immune-mediated tumour rejection [4].

The preclinical success of the combination of anti-CTLA-4 antibody and IR was mirrored by abscopal responses seen in metastatic melanoma and non-small-cell lung cancer (NSCLC) patients irradiated in one lesion during ipilimumab therapy. These clinical observations strongly suggest that the effects of IR identified in experimental models are relevant to patients. IR can stimulate the anti-tumor immune response, increasing the proportion of patients who respond to checkpoint blockade treatment, an hypothesis currently being tested in clinical trials. The same pattern of abscopal responses has been observed in preclinical models was also demonstrated in clinical cases of lymphomas and breast cancers treated by combinations of RT and toll-like receptor agonists. Finally, blocking tumour growth factor beta (TGF-beta) during RT preclinically has demonstrated abscopal effects that have been confirmed in one patient accrued to a trial of antihuman TGFb antibody fresolimumab and RT. While promising, this evidence remains preliminary and warrants more research to define the optimal combinations of immunotherapy and RT, to best exploit this novel role of ionising radiation [3].

Conflict of interest statement The content to be presented at 17th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress does not pose any conflict of interest. R E F E R E N C E S

[1] Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. JNCI 2013;105(4):256–65. [2] Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol 2009;10(7):718–26. [3] Formenti SC, Demaria S. Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys 2012;84(4):879–80. [4] Ruocco MG, Pilones KA, Kawashima N, Cammer M, Huang J, Babb JS, et al. Suppressing T cell motility induced by antiCTLA-4 monotherapy improves antitumor effects. J Clin Invest 2012;122(10):3718–30.

* Corresponding author: Address: 160 East 34th Street Room 123 New York, NY 10016, USA. Tel.: +1 212 731 5039. E-mail addresses: [email protected] (S.C. Formenti), [email protected] (S. Demaria). 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.040

At what price do we treat patients with testicular cancer? Gedske Daugaard

*

Copenhagen University Hospital, Department of Oncology, Rigshospitalet, Copenhagen, Denmark

In 2013 testicular cancer (TC) represents the most curable solid tumour. The high cure rate is associated with a significant long-term morbidity. Long-term effects after TC treatment can be divided into life-threatening (e.g. secondary tumours and cardiovascular disease) or effects on single organs (e.g. nephro-, neuro- and pulmonary toxicity, hypogonadism or decreased fertility). Psychosocial effects are also a major issue, with fatigue, influence on sexuality, work, cognitive function, quality of life, lifestyle factors, etc. Some of these side effects are discussed below, with a focus on future studies. Testicular cancer survivors are at significantly increased risk of solid tumours for at least 35 years after treatment, with a higher incidence in patients who have had a seminoma compared to non-seminoma [1,2]. However, published studies lack detailed information concerning treatment or refer to formerly used treatments. Several studies have demonstrated increased risk of cardiovascular disease [3–7]. A Norwegian study found a 5.7-fold higher risk for coronary artery disease after bleomycin, etoposide and cisplatin (BEP) treatment, with a median observation time of 19 years [3]. Hypogonadism, hyperlipidaemia [4] and metabolic syndrome [4,7] have been mentioned as risk factors. Metabolic syndrome in particular could be linked to subclinical testosterone deficiency. It is necessary to increase our knowledge concerning the impact of cisplatin-based chemotherapy, lifestyle factors (diet, tobacco, physical activity), hypogonadism, family history concerning cardiovascular disease (CVD), alcohol, abnormal blood samples and gene changes on the development of cardiovascular disease in TC patients. Given the increased incidence of CVD in TC patients it would be relevant to look at genetic markers which in the general population have been found to predispose to these diseases. To develop risk models that include the above-mentioned factors, international cooperation is needed. This could make it possible to stratify TC patients into risk groups and develop evidence-based intervention according to the risk factors. Testicular cancer patients should be tested for subclinical hypogonadism. We know that after treatment, the serum tes-

tosterone concentration is in the lower part of the normal range [8] and that 12–16% of long-term survivors have developed hypogonadism. Most younger TC patients exhibit some dysfunction of the Leydig cells, which is compensated by an increase in luteinising hormone (LH) levels. Whether this compensation is adequate in elderly TC patients is not known. The clinical significance of low testosterone levels is under discussion, but most people believe that a sustained reduction in testosterone is a contributing factor in the development of metabolic syndrome, type-2 diabetes, osteoporosis, decreased quality of life and premature ageing [9]. Hypogonadism could be a significant and independent predictor for the development of CVD, and if this is the case, testosterone replacement should be examined. All TC patients treated with cisplatin will experience a decline in glomerular filtration rate (GFR). This reduction will in some patients be reversible, whereas in others GFR shows a permanent decrease of up to 30% or more [10,11]. There is no long-term monitoring of renal function in TC patients treated with cisplatin. Experimental and clinical data suggest that hypomagnesaemia is important for the development of nephrotoxicity [12]. There are several unanswered questions related to nephrotoxicity in this group of patients. It is unknown whether the natural age loss in GFR is accelerated in TC patients treated with platinum or whether the nephrotoxicity is exacerbated in older platinum-treated TC patients. Another important issue to clarify is the influence of a decline in GFR on the development of cardiovascular disease and death from all causes. The high survival rate and young age of patients with TC entails that the treatment effect on reproductive function, fertility and offspring health is a very significant factor. Affected Sertoli-cell function and impaired Leydig-cell function in a subset of TC patients result from testicular dysgenesis syndrome [13] which may explain the increased incidence of oligo-and azospermi in TC patients both before and after orchiectomy, but before further treatment. Most long-term survivors after treatment for TC can become biological fathers without medical assistance [14]. Yet

* Tel.: +45 35454677. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.045

272

EJC SUPPLEMENTS

the 10-year paternity rate is reduced by 30% compared with the normal population. All studies concerning gonadal function in TC patients is based on data from a single department, with a limited number of patients and few details about the treatment. With the development of modern assisting reproductive techniques, even men with significant gonadal dysfunction will be able to have children. Cryopreservation of semen, optimally performed before orchiectomy, is offered in most places in order to increase the likelihood of subsequent fatherhood. In view of the increased opportunity and use of frozen semen for later artificial insemination, it is important to clarify whether pregnancies obtained with frozen semen of low quality are subject to more abortions, stillbirths or deformed children. These data will be essential in order to advise the TC patients. Larger-scale data concerning fertility in patients with TC treated with either surveillance or chemotherapy (three or four cycles of BEP) are needed. Data regarding the factors leading to long-term side effects of treatment remain scarce. Molecular testing methods might help in identifying patients at high risk for therapy-related complications and guide risk-adapted screening and intervention strategies. In recent years, screening for variations in polymorphisms has proved to be a valuable tool to investigate the genetic predisposition for late effects. There is a relatively high incidence of single-nucleotide polymorphisms (SNPs) in genes which affect the cellular response in relation to the cytotoxic treatment for TC [15]. In order to gain further knowledge on the development of late effects in TC patients we need to have detailed information about treatment, to include genetic research methods, and to study side effects over time. The hope is that increased knowledge can lead to interventional studies with reduction or prevention of late effects.

R E F E R E N C E S

[1] Travis LB, Fossa˚ SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 2005;97:1354–65.

1 1 ( 20 1 3) 2 7 1–27 2

[2] Hemminki K, Liu H, Sundquist J. Second cancers after testicular cancer diagnosed after 1980 in Sweden. Ann Oncol 2010;21:1546–51. [3] Haugnes HS, Wethal T, Aass N, et al. Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J Clin Oncol 2010;28:4649–57. [4] de Haas EC, Altena R, Boezen HM, et al. Early development of the metabolic syndrome after chemotherapy for testicular cancer. Ann Oncol 2013;24:749–55. [5] van den Belt-Dusebout AW, Nuver J, de Wit R, et al. Longterm risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 2006;24(3):467–75. [6] Meinardi MT, Gietema JA, van der Graaf WT, et al. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 2000;18(8):1725–32. [7] Haugnes HS, Aass N, Fossa SD, et al. Components of metabolic syndrome in long-term survivors of testicular cancer. Ann Oncol 2007;18:241–8. [8] Turek PJ, Lowther DN, Carroll PR. Fertility issues and their management in men with testis cancer. Urol Clin North Am 1998;25(3):517–31. [9] Yeap BB. Testosterone and ill-health in aging men. Nat Clin Pract Endocrinol Metab 2009;5(2):113–21. [10] Fossa SD, Aass N, Winderen M, Bormer OP, Olsen DR. Longterm renal function after treatment for malignant germ-cell tumours. Ann Oncol 2002;13(2):222–8. [11] Hansen SW, Groth S, Daugaard G, Rossing N, Rorth M. Longterm effects on renal function and blood pressure of treatment with cisplatin, vinblastine, and bleomycin in patients with germ cell cancer. J Clin Oncol 1988;6(11):1728–31. [12] Lajer H, Kristensen M, Hansen HH, et al. Magnesium depletion enhances cisplatin-induced nephrotoxicity. Cancer Chemother Pharmacol 2005;56(5):535–42. [13] Bay K, Asklund C, Skakkebaek NE, Andersson AM. Testicular dysgenesis syndrome: possible role of endocrine disrupters. Best Pract Res Clin Endocrinol Metab 2006;20(1):77–90. [14] Brydoy M, Fossa SD, Klepp O, et al. Paternity following treatment for testicular cancer. J Natl Cancer Inst. 2005;97:1580–8. [15] Maffei F, Carbone F, Angelini S, et al. Micronuclei frequency induced by bleomycin in human peripheral lymphocytes: correlating BLHX polymorphism with mutagen sensitivity. Mutat Res 2008;639(1–2):20–6.

Collaborative international oncology nursing research is improving but still has a long way to go! Experiences, possibilities and challenges Carol Tishelman

*

Karolinska Institutet, Department of Learning, Informatics, Management and Ethics, Medical Management Center, Stockholm, Sweden

In this interactive teaching lecture I will draw on my experiences from a variety of successful and less successful international research projects, with roles as researcher, collaborator and advisor. Topics that will be addressed include the process from vision to collaboration, benefits of collaboration, the need for and qualities of leadership in driving such projects, key components of collaborative endeavours and challenges faced in forming and carrying out research

collaborations. Discussion of these topics will be based on ongoing and completed collaborative projects. Reflections from the participants are welcome throughout the session.

Conflict of interest statement None declared.

* Tel.: +46 (0) 8 52483744. E-mail address: [email protected] 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.047

Epidermal growth factor receptor targeting and its role for individualisation in radiation oncology Mechthild Krause

*

Dept. of Radiation Oncology and OncoRay National Center for Radiation Research in Oncology, Medical Faculty and University Hospital C.G. Carus, Technische Universita¨t, Dresden, Germany German Cancer Consortium (DKTK), Dresden, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany Helmholtz Center Dresden-Rossendorf, Germany

Because of its over-expression in many human tumours and its association with a poor prognosis, the epidermal growth factor receptor (EGFR) is used as a therapeutic target in clinical routine and in clinical trials. Two major classes of inhibitors are used: anti-EGFR antibodies and EGFR tyrosine kinase inhibitors (TKIs). On simultaneous application of the anti-EGFR antibody cetuximab with radiotherapy in head and neck squamous-cell carcinoma (HNSCC) patients, an improvement in locoregional tumour control and survival has been shown as compared with radiotherapy alone, leading to the approval of this drug as the first molecular targeted agent in a curative radio-oncological setting. However, so far there is no hint of a superiority of this combination over simultaneous cisplatin-based radiochemotherapy; thus, both treatments are used today as alternative schedules. While it is evident from preclinical as well as from clinical data that a major heterogeneity exists among the responses of individual patients to the combined treatment, apart from skin reactions under cetuximab treatment, there is so far no validated biomarker predicting response to cetuximab-based combined treatment, nor to cisplatin-based radiochemotherapy. Establishing predictive biomarkers would highly increase efficacy of the treatment due to the positive selection of patients. Some conclusions can currently be drawn from translationally oriented studies: at least for HNSCCs (others have not been well investigated), cetuximab application during radiotherapy improves locoregional tumour control in many but not all individual tumours, with individually impressive responses. For EGFR–TKI all local tumour control studies have been negative so far, whereas palliative effects have been shown in most HNSCCs. A promising candidate biomarker

for the effect of combined radiotherapy and cetuximab in HNSCC is genetic EGFR over-expression measured by the fluorescence in situ hybridization (FISH) test. This marker has to be further validated in clinical settings, as well as for other tumour entities or combination schedules. Because of interactions between the treatment modalities, such biomarkers can be different between single-modality and combinedmodality treatments.

Conflict of interest statement None declared.

Acknowledgements Funding was supplied by the Deutsche Forschungsgemeinschaft (DFG, Ba1433), German Federal Ministry of Education and Science (BMBF).

F U R T H E R R E A D I N G

[1] Gurtner K, Deuse Y, Bu¨tof R, et al. Diverse effects of combined radiotherapy and EGFR inhibition with antibodies or TK inhibitors on local tumour control and correlation with EGFR gene expression. Radiother Oncol 2011;99:323–30. [2] Krause M, Gurtner K, Deuse Y, Baumann M. Heterogeneity of tumour response to combined radiotherapy and EGFR inhibitors: Differences between antibodies and TK inhibitors. Int J Radiat Biol 2009;85:943–54.

* Address: Universita¨tsklinikum Carl Gustav Carus, Dept. of Radiation Oncology, Fetscherstr. 74, DE-01307 Dresden, Germany. Tel.: +49 (0) 351 458 5292. E-mail address: Mechthild.Krause@uniklinikum-dresden. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.049

From novel insights in molecular biology to targeted treatment approaches in head and neck cancer Kevin J. Harrington

*

The Institute of Cancer Research, London, United Kingdom

Squamous-cell carcinoma of the head and neck is the fifth commonest neoplasm worldwide. Over 50% of patients present with stage III/IV disease: so-called locally advanced head and neck cancer (LAHNC). For LAHNC, the treatment paradigm has shifted from mutilating, ablative surgery towards organ-preserving concomitant cisplatin-based chemoradiotherapy [1]. Compared with surgery, chemoradiotherapy delivers equivalent or better locoregional control and disease-free survival with significantly better functional outcomes [1]. Nonetheless, 5-year disease-free and overall survival (30–40%) rates are suboptimal [2]. Strategies to improve outcomes by escalating conventionally delivered radiotherapy and/or cytotoxic chemotherapy are appealing, but they pose unacceptable risks of severe acute and late normal tissue damage and threaten chronic structural, cosmetic and functional deficits that negatively impact quality of life [3]. Recent technical developments in physical targeting of radiation delivery, including intensity-modulated and image-guided therapy, offer a way of safely escalating tumour dose without exceeding normal tissue tolerances. Also, a clearer understanding of the radiation-induced DNA damage response (RIDDR) opens up the possibility of developing tumour-selective biological response modifiers to enhance the effect of radiotherapy/chemoradiotherapy. The potential value of such therapies has been proven by the translation of therapy targeted to the epidermal growth factor receptor (EGFR), cetuximab, from preclinical studies to a positive phase III trial in combination with radiation [4]. In addition, smallmolecule tyrosine kinase inhibitors have been tested [5,6]. Recently, biological studies have characterised LAHNC as a disease spectrum, divisible into different prognostic groups on the basis of demographic (tobacco exposure), clinical/ radiological (T and N stage) and molecular pathological (human papillomavirus (HPV) status) variables [7]. In addition, we are beginning to understand the molecular landscape of LAHNC more clearly [8]. As a result, we can escape the standard model whereby all patients receive treatment according to a ‘one size suits all’ philosophy. Instead, we are moving to-

wards treatment individualisation according to prognostic risk group. Until recently, it was accepted that the standard of care for patients with LAHNC was concomitant cisplatin-based chemoradiotherapy. However, recent data on prognostic subgroups suggest that this is a significant oversimplification: patients with poor prognosis disease may receive suboptimal treatment, while those with good prognosis disease may be overtreated with unnecessary risks of toxicity. Therefore, there has been a realignment towards developing effective, molecularly targeted strategies that offer personalised treatment to individual patients based on prognostic factors. The clearest view of prognosis comes from post hoc analysis of patients with oropharyngeal cancers treated in the RTOG-0129 phase III trial [7]. This study defined prognostic groups using specific demographic, clinical/radiological and molecular pathological characteristics: (1) poor-risk disease affected 27% of patients with heavy tobacco use, T4 tumours and HPV/p16INK4a-negative status; (2) low-risk disease occurred in 43% with HPV-positive status and little prior tobacco exposure (or, if >10 pack-year smoking history, by N0–N2a nodal status) and (3) intermediate-risk disease was represented by the 30% with either HPVpositive tumours and >10 pack-year tobacco exposure and N2b/N3 neck disease or HPV-negative tumours and 60% [6]. Currently, a sequential chemotherapy approach containing anthracycline–cyclophosphamide and a taxane plus trastuzumab is the better choice for patients with HER2-positive disease. The addition of pertuzumab to this sequence, or to a taxane–carboplatin combination, could be a future option when it becomes available.

4.

TNBC

The simultaneous application of docetaxel, doxorubicin and cyclophosphamide (TAC) for six cycles accounts for the highest pCR rates in TNBC patients in the German neoadjuvant studies, particularly for patients with an early response after only two cycles [7]. As shown in the GeparQuinto study, the treatment effect might be further improved by adding bevacizumab to neoadjuvant chemotherapy [8]. However, even considering the nonconfirmatory results of the NSABP B40 trial [9], the use of this anti-angiogenic drug in the neoadjuvant setting should be further investigated. In the near future the role of bevacizumab and carboplatin will be better defined by the GeparSixto study [10] which is investigating bevacizumab given simultaneously to weekly carboplatin, paclitaxel, and pegylated doxorubicin in TNBC and HER2-positive patients; and by the CALGB 40603 study [11] which is evaluating three weekly carboplatin and bevacizumab in a 2 by 2 factorial design in patients treated with weekly paclitaxel followed by dose-dense doxorubicin/ cyclophosphamide.

* Corresponding author: Tel.: +49 6102 7480 411. E-mail address: [email protected] (G.von Minckwitz). 1359-6349/$ - see front matter Copyright  2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.043

EJC SUPPLEMENTS

1 1 ( 2 0 1 3 ) 2 8 4 –2 8 5

285

Table 1 – Different neoadjuvant approaches according to breast cancer subtypes. Subtype

Neoadjuvant treatment

Reference

HR-positive disease

EC–Pw TAC · 2 ! response-guided chemotherapy

Meta-analyses of several neoadjuvant studies2–4 GeparTrio5

HER2-positive disease

EC(H)–TH FECHP–TH or TCH (plus P if available)

Meta-analyses of several neoadjuvant studies2–4 Tryphaena6

TNBC

TAC EC–Pw Role of bevacizumab is uncertain

Meta-analysis of seven German neoadjuvant studies7 Meta-analyses of several neoadjuvant studies [2–4] GeparQuinto8 and NSABP 409Waiting for GeparSixto10 and CALGB 4060311 Waiting for GeparSixto10 and CALGB 4060311

Role of carboplatin is uncertain

E, epirubicin; C, cyclophosphamide; Pw, paclitaxel weekly; T, docetaxel; A, doxorubicin; F, 5-fluorouracil; H, trastuzumab; P, pertuzumab; TNBC, triple-negative breast cancer.

5.

Conclusion

In conclusion, considering that HER2-positive/HR-negative and TNBC patients who achieve pCR showed a prognosis comparable to that of patients with luminal-A-like tumours [2], a neoadjuvant strategy tailored to different breast cancer subtypes can completely change the natural history of some cancers.

Conflict of interest statement Dr. von Minckwitz has received consultancy, speakers’ honoraria, and research funding from Roche and Sanofi-Aventis. Dr. Fontanella has no conflict of interest to disclose.

R E F E R E N C E S

[1] Available from: http://www.nccn.org/professionals/ physician_gls/pdf/breast.pdf [assessed 14.05.13]. [2] von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012 May 20;30(15):1796–804. [3] Houssami N, Macaskill P, von Minckwitz G, Marinovich ML, Mamounas E. Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer 2012;48(18):3342–54.

[4] von Minckwitz G, Untch M, Nu¨esch E, et al. Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neoadjuvant chemotherapy trials. Breast Cancer Res Treat 2011;125(1):145–56. [5] von Minckwitz G, Ku¨mmel S, Vogel P, et al. German Breast Group. Intensified neoadjuvant chemotherapy in earlyresponding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst 2008;100(8):552–62. [6] Schneeweiss A, Chia S, Hickish T, et al. Neoadjuvant pertuzumab and trastuzumab concurrent or sequential with an anthracycline-containing or concurrent with an anthracycline-free standard regimen: a randomized phase II study (TRYPHAENA). Cancer Res 2011;71(24 Suppl. 3). [7] von Minckwitz G, Mamouhdian-Dekordi C, Loibl S, et al. Response characteristics and overall survival of 781 patients with triple-negative breast cancer – a meta-analysis on 7 German neoadjuvant studies. AACR Annual Meeting 2013. [8] von Minckwitz G, Eidtmann H, Rezai M, et al. German Breast Group; Arbeitsgemeinschaft Gyna¨kologische Onkologie– Breast Study Groups. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 2012;366(4):299–309. [9] Bear HD, Tang G, Rastogi P, Geyer Jr CE, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 2012;366(4):310–20. [10] Available from: http://clinicaltrials.gov/show/NCT01426880 [accessed 14.05.13]. [11] Available from: http://clinicaltrials.gov/show/NCT00861705 [accessed 14.05.13].

Surgical management of neuroendocrine tumour (NET) liver metastases Per Hellman

*

University Hospital, Department of Surgery, Uppsala, Sweden

Neuroendocrine tumours (NETs) usually have an indolent course, developing slowly over many years, and when there is a lack of overt hormonal symptoms they may have been present for a considerable period of time before diagnosis. Therefore, NETs are commonly found with metastatic disease at diagnosis, especially in the most common variant smallintestinal NETs (SI-NETs). Surgical treatment of NETs varies somewhat according to site of origin and extent of disease. Surgical treatment of liver metastases is generally indicated if there are less than about five tumours, if they are confined to one lobe or in the case of large tumours as a debulking option to reduce hormonal release. However, there are several alternative options. First of all, stabilisation of disease is important, usually achieved by offering biotherapy (SI-NETs) or chemotherapy (pancreatic or pulmonary NETs). In addition, treatment with 177luthetium-labelled somatostatin analogues in tumours expressing somatostatin receptors has emerged as a possible option for initial treatment. After stabilisation of the disease, or even reduction of the tumour burden, often achieved by these treatments, surgery may become an option. A likewise targeted metastasis-directed therapy is ablation by radiofrequency (RFA), microwave (MW) or recently also irreversible electroporation (IRE). Another available option is hepatic artery embolisation. Therefore, surgical management of liver metastases may be offered at different stages of the disease. In some cases the goal is total eradication of metastases from the liver, in other cases as another method to keep the disease ‘under control’ or as a debulking procedure to reduce hormonal levels. RFA or MW for SI-NETs has been evaluated and found to be safe, to reduce hormonal levels, and to reduce symptoms such as diarrhoea and abdominal pain. However, there seems to be no improvement on survival, although no randomised trial to test this has yet been conducted. Surgery has classically involved standard resections such as segmentectomies or hemihepatectomy, but recently a more local approach has been utilised as an alternative to the likewise local RFA or MW. No studies have compared liver surgery for NETs with the alternatives, but studies have

demonstrated the safety of – and clear benefit as a result of – surgery as a debulking procedure. Studies in SI-NET have shown that the recurrence rate of liver metastases is very high. In careful microscopic evaluations of resected liver specimens it is clear that there are almost always several previously unrecognised metastases present, perhaps indicating the impossible goal of reaching microscopic R0. In pancreatic NETs the situation may be different. Unless diffusely spread, R0 may be achieved in the liver, and if combined with proper chemotherapy an impressively stable disease may be achieved compared with previously. Liver transplantation has been advocated in patients with pancreatic NETs, Ki67 < 10% and lack of extrahepatic disease. In practice, however, this situation is rather rare, since lymph-node and skeletal metastases are often present, nowadays visualised with the more sensitive tools of today (Ga-DOTATOC/TATE PET). For SI-NET, liver transplant would be theoretically preferable considering the high rate of unknown liver metastases, but the survival for such patients has a median of >20 years, raising doubts about whether liver transplant is an option. Indeed, the metastases in SI-NETs commonly also occur at other sites than in the liver – but may still be controlled with the appropriate biotherapy treatment, as well as with 177Lu in certain cases. Indeed, there are reports of very successful liver transplant case series, but also cases with recurrence of disease in the new liver associated with short survival. Overall, no comparative or randomised studies are available to support any evidence-based recommendations. There are several patient case series describing long survival and improvement of symptoms after liver surgery, but these are of small value because of lack of comparisons. On the other hand, liver surgery or ablative procedures may still be chosen by the individual patient when offered, as a variant of personalised medical care.

Conflict of interest statement None declared.

* Tel.:+46 186114617. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.050

Application of sentinel nodes in gynaecological cancer therapy M.H.M. Oonk, A.G.J. van der Zee

*

University Medical Centre Groningen, Department of Gynaecologic Oncology, Groningen, The Netherlands

The sentinel-node procedure was introduced in cancer therapy in order to reduce the morbidity that is associated with full lymphadenectomy without compromising survival rates. In gynaecological cancer the application of the sentinel-node procedure has been investigated in vulvar, cervical, and endometrial cancer. In vulvar cancer, the Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V) showed that it was safe to omit inguinofemoral lymphadenectomy in patients with a negative sentinel node. Eligible patients who underwent the procedure had unifocal squamous-cell cancer of the vulva, with a maximum diameter of 4 cm and no suspicious groin nodes at palpation. In the case of a negative sentinel node, no inguinofemoral lymphadenectomy was performed, and patients were followed up regularly. Both short-term and long-term treatment-related morbidities were significantly lower when only the sentinel node was removed. Groin recurrences were observed in 2.3% of the patients with a negative sentinel node [1]. An analysis of the patients with a positive sentinel node showed an increasing risk for involvement of non-sentinel nodes with increasing size of the metastasis in the sentinel node. Furthermore, the prognosis was significantly worse for patients with sentinel-node metastases >2 mm [2]. More recently Levenback and colleagues published the results of the Gynaecologic Oncology Group study on the sentinel node procedure in vulvar cancer (GOG-173). They included 452 patients; all patients underwent inguinofemoral lymphadenectomy after sentinel-node detection. They found a false-negative predictive value of 3.7%. In women with a tumour 20% of their total body weight during or following radiotherapy are at an increased risk of toxicity and mortality. Stage 3 or 4 disease and smoking more than 20 cigarettes a day should be reason enough for early enteral feeding. A prophylactic percutaneously placed endoscopic gastrostomy (PEG) feeding tube is also beneficial when there is pretreatment weight loss [2]. Nutrition screening is the process of identifying patients with characteristics commonly associated with nutritional problems that may require full nutritional assessment. Screening can be applied to all patients. The malnutrition screening tool (MST) is a validated, quick and simple nutrition screening tool. The patient-generated subjective global assessment (PG-SGA) can be applied for a full nutritional assessment [1]. The identification of baseline risk factors to assess a patient’s fragility or ability to tolerate treatment is desirable to predict outcome of chemotherapy toxicity, not only for medically unfit patients but also amongst patients with an apparently good medical condition, since the high inter-individual variability in drug exposure remains an unresolved issue. Chemotherapy-induced DNA damage might become more cytotoxic to normal tissue in the presence of perturbations of the cellular immune response because of high protein catabolism and stimulation of acute-phase protein responses (APPRs). The nutritional and inflammatory status (NIS) appears to correlate with increased risk of severe haematolog-

ical toxicity following anticancer chemotherapy. This status takes in account (1) C-reactive protein, (2) alpha-1-acid glycoprotein, (3) albumin and (4) prealbumin: NIS = (1 · 2)/ (3 · 4) [3]. Malnutrition has been associated with changes in drug disposition, including changes in absorption, protein binding, hepatic metabolism and renal elimination. In malnourished patients reduced concentrations of plasma proteins may significantly increase the likelihood of toxicity from the administrations of agents that are highly protein-bound, such as prednisolone, etoposide, teniposide, cisplatin, paclitaxel and SN-38 [4]. Anticancer treatment can induce a poor nutritional status by inducing nausea, vomiting and anorexia and gastrointestinal disorders as mucositis and diarrhoea [4]. Reversible lactose intolerance – associated with diarrhoea, flatulence and poor nutritional status – is not infrequent in patients treated with chemotherapy based on 5-fluorouracil (5-FU). Hypolactasia can easily be diagnosed with a lactose tolerance test. Dietary lactose restriction might improve tolerability of treatment [5]. Malabsorption may be caused not only by fluorouracil but also by other drugs affecting cell proliferation such as thioguanine, methotrexate, vinca’s alkaloid, actinomycin D, hydroxyurea and daunomycin [6].

2. Influence of nutritional deficiencies on chemotherapy and vice versa Trace elements consist mostly of metal ions which act mainly as basic components of essential enzymatic systems or proteins that play major roles in the physiology of the gastrointestinal tract (Jackson, 1989). Studies suggest that trace elements serve as cofactors in several metabolic pathways, and a decrease in their concentration may facilitate the malnutrition process that takes place in cancer patients. Negative acute-phase reactants such as selenium and zinc are decreased in cancer patients, whereas serum levels of copper are increased. Selenium deficiency may interfere with

* Tel.: +32 32803340; fax: +32 32810719. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright  2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.057

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free-radical-mediated damage. Zinc regulates the function of cytochromes, stabilizes plasma membranes, reduces lipid peroxidation and has a role in the detoxification of ammonia. A deficiency in zinc potentiates the toxicity of other metals and decreases the plasma values of vitamin A. Supplementation of these trace elements can delay cachexia with its consequent depression of the immune system, influencing the neoplastic process and the success of chemotherapy [7]. Cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), can induce an inappropriate urinary excretion of magnesium through the inhibition of reabsorption of magnesium in the ascending loop of Henle, since EGFR is strongly expressed in the kidney [8]. This leads to symptomatic hypomagnesaemia, a side effect also commonly known to be associated with the use of cisplatin. Cachectic patients with decreased dietary carnitine uptake may develop carnitine deficiency when treated repeatedly with chemotherapies that include cisplatin. They have a tenfold increase in renal carnitine excretion [9]. Pemetrexed, a multitargeted antifolate, is associated with life-threatening toxicity, especially myelosuppression, if not administrated after supplementation with folic acid and vitamin B12. One week prior to commencing pemetrexed, folic acid (0.5 mg by mouth each day) and vitamin B12 (1 mg by intramuscular injection every 9 weeks) should be given [10].

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hormonal treatments such as tamoxifen, and with erythropoietic growth factors, estramustin or thalidomide.

4.

Conclusion

Nutrition and nutritional status are influenced by the presence of cancer but also have an important influence on anticancer treatment and treatment outcome. It is important that the oncologist has an insight into the possible interactions and complications that nutritional agents may have with chemotherapeutic agents. The ability to identify and locate reliable information regarding dietary supplements is vital. The use of more than one reference is necessary to complete the analysis of dietary supplements for a patient. Counselling patients with cancer about dietary supplements requires a systematic thought process that considers the available theories and data, as well as the patient’s views about these agents [13]. More attention should be paid to patient nutritional status, and cooperation with a dietician is essential in the care of the cancer patient.

Conflict of interest statement None declared.

3. Influence of nutritional supplements on chemotherapy

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More than 80% of the patients with cancer surveyed in 2000 in the United States reported using complementary and alternative medicine (CAM) [11]. While the body of literature related to the use of CAM is growing, the extrapolation and application to patient care remain complex. Clinicians must establish whether the supplement is an antioxidant, is an anticoagulant or procoagulant, has immunosuppressive or immunomodulatory properties, has hormonal properties, has known safety issues and has known or theoretical drug interactions [12]. Antioxidants represent one of the largest categories of dietary supplements. Reactive oxygen species (ROSs) are a natural consequence of living in an aerobic environment. Oxidative stress occurs when natural defence systems are inadequate to combat the production of ROSs. Antioxidants could be protective against the adverse effects of chemotherapy, but some of these agents rely for their antineoplastic activity on the production or interaction with ROSs. Agents with a high reliance on ROSs for their antineoplastic activity are alkylating agents and mitomycin C. Mitoxanthrone is less likely to be dependent on ROSs. The use of dietary supplements with anticoagulant properties, alone or concomitantly with conventional anticoagulants or antiplatelet medication, may pose a risk for bleeding due to additive or synergistic effects on the coagulation pathway. Agents with coumarin constituents – such as angelica root, agents that inhibit platelets such as panax ginseng, agents with salicylate constituents such as black cohosh, garlic, ginkgo, saw palmetto – may increase the risk of bleeding. Supplements with procoagulant properties should be avoided with

[1] Isenring E, Cross G, Daniels L, Kellett E, Koczwara B. Validity of the malnutrition screening tool as an effective predictor of nutritional risk in oncology outpatients receiving chemotherapy. Support Care Cancer 2006;14:1152–6. [2] Kiyomoto D. Head and neck cancer patients treated with chemo-radiotherapy require individualized oncology nutrition. J Am Diet Assoc 2007;107:412–5. [3] Alexandre J, Gross-Goupil M, Falssard B, et al. Evaluation of the nutritional and inflammatory status in cancer patients for the risk assessment of severe hematological toxicity following chemotherapy. Ann Oncol 2003;14:36–41. [4] Murry D, Riva L, Poplack D. Impact of nutrition on pharmacokinetics of anti-neoplastic agents. Int J Cancer 1998;11:48–51 [Supplement]. ¨ sterlund P, Ruotsalainen T, Peuhkuri K, et al. Lactose [5] O intolerance associated with adjuvant 5-fluorouracil-based chemotherapy for colorectal cancer. Clin Gastroenterol Hepatol 2004;2:696–703. [6] Trier JS. Morphologic alterations induced by methotrexate in the mucosa of the human proximal in. [7] Federico A, Iodice P, Federico P, et al. Effects of selenium and zinc supplementation on nutritional status in patients with cancer of digestive tract. Eur J Clin Nutr 2001;55:293–7. [8] Schrag D, Chung KY, Flombaum C, Saltz L. Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst 2005;97:1221–4. [9] Heuberger W, Berardi S, Jacky E, Pey P, Kra¨henbu¨hl S. Increased urinary excretion of carnitine in patients treated with cisplatin. Eur J Clin Pharmacol 1998;54:503–8. [10] Li KM, Rivory LP, Clarke SJ. Pemetrexed pharmacokinetics and pharmacodynamics in a phase 2 study of doublet chemotherapy with vinorelbine: implications for further

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optimisation of pemetrexed schedules. Br J Cancer 2007;97:1071–6. [11] Richardson MA, Sanders T, Palmer JL, et al. Complementary/ alternative medicine use in a comprehensive cancer center and the implications for oncology. J Clin Oncol 2000;18:2505–14.

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[12] Michaud LB, Karpinski JP, Jones KL, Esperito J. Dietary supplements bin patients with cancer: risks and key concepts, Part 1. Am J Health Syst Pharm 2007;64:369–81. [13] Michaud LB, Karpinski JP, Jones KL, Esperito J. Dietary supplements bin patients with cancer: risks and key concepts, Part 2. Am J Health Syst Pharm 2007;64:467–80.

The best treatment for older patients with breast cancer Natalie Turner a, Elena Zafarana a, Giuseppina Sanna a, Giuseppe Mottino b, Laura Biganzoli a,* a b

Hospital of Prato, Istituto Toscano Tumori, Prato, Italy Hospital of Prato, Prato, Italy

1.

Introduction

One of the biggest risk factors for the development of breast cancer is age, and over 40% of all breast cancers diagnosed are in women aged 65 years or older [1]. Despite this, there are few standardised guidelines for the management of older breast-cancer patients, primarily due to the lack of level-I evidence and the lack of representation of older women in adjuvant therapy trials. Thus clinicians are often required to make treatment decisions for elderly patients in the face of uncertainty. This often leads to undertreatment, or less frequently, overtreatment of elderly patients, with resultant poorer outcomes. In order to address this issue, a task force created by the International Society of Geriatric Oncology (SIOG) and the European Society of Breast Cancer Specialists (EUSOMA) has developed a set of evidence-based guidelines for the management of breast cancer in elderly individuals [2]. It is important to note that these guidelines are predominantly applicable only to elderly patients who are fit, rather than those who are less fit or frail, due to the scarcity of data relating to treatment of this latter group. Key recommendations are summarised as follows. •

•

For an older individual with breast cancer it is critical that all management decisions take into account physiological age, life expectancy, potential risks versus absolute benefits, treatment tolerance, patient preference and potential barriers to treatment. Elderly breast-cancer patient management should involve collaboration between geriatricians and oncologists. Elderly patients are at higher risk for competing comorbidities, which may not be evident on oncological assessment. Comprehensive evaluation of functional status with a multidomain geriatric assessment (CGA) is ideal, although this may not be possible in all patients. Alterna-

tively, it is reasonable to perform a functional screening assessment to identify which patients are at increased risk for functional deficits on the extended CGA. In patients in whom reversible functional deficits are detected, proactive management of these can improve quality of life and survival. Similarly, identification of interval decrease in functional status through the use of repeated geriatric assessments allows appropriate intervention and potentially improved outcomes.

2.

•

•

•

Early breast cancer

Surgical options for patients 70 years or older should be equivalent to those of younger patients, with age itself not an indication for less-than-standard surgical management. In some older patients it might be reasonable to omit either sentinel lymph-node biopsy or completion axillary lymph-node dissection, though this is an area of ongoing debate. All elderly patients undergoing breast-conserving surgery should be offered whole breast irradiation as a means to significantly reduce local relapse rates. Elderly patients with high-risk tumour (T3–4 or at least four lymph nodes involved) should be considered for post-mastectomy radiotherapy. Treatment of estrogen-receptor (ER) positive breast cancer with endocrine therapy alone is a suitable treatment strategy only in an elderly individual who has a limited life expectancy (less than 3 years), who is considered unfit for surgery after optimisation of medical conditions, or who refuses surgery. Geriatrician input to guide the management of comorbidities and to accurately assess life expectancy is strongly recommended.

* Corresponding author: Tel.: +39 0574 434766. E-mail address: [email protected] (L. Biganzoli). 1359-6349/$ - see front matter Copyright  2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.056

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•

•

•

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Tamoxifen and aromatase inhibitors have similar efficacy in older as in younger patients and are recommended as initial adjuvant hormone therapies. The choice between tamoxifen or aromatase inhibitors should be made by balancing the slightly higher efficacy of aromatase inhibitors with the increased vulnerability of elderly patient to their toxicities. For patients who commence on tamoxifen, a switch from tamoxifen to aromatase inhibitor after 2– 3 years should be considered on the basis of treatment tolerability. Similarly, for healthy elderly patients, extended endocrine therapy with an aromatase inhibitor after 5 years of tamoxifen is reasonable. In elderly patients with very low-risk tumours (pT1aN0) or severe comorbidities, the risks and toxicities of endocrine therapy may outweigh the benefits; in these circumstances it may be reasonable to omit adjuvant endocrine therapy. Fit elderly patients gain as much benefit as younger patients from adjuvant chemotherapy. Chemotherapy decisions should be made based on potential benefits, which are highest in node-positive, hormone-negative disease, compared with risks and toxicities. Four cycles of an anthracycline-containing regimens are usually preferred over cyclophosphamide methotrexate 5-fluorouracil (CMF). Substitution of anthracycline with taxane is also a reasonable option to reduce the risk of cardiac toxicity. Adjuvant trastuzumab in combination with chemotherapy should be offered to all elderly patients with HER2-positive breast cancer, without cardiac disease, and who are suitable for chemotherapy treatment. Use of single-agent trastuzumab in patients not suitable for chemotherapy might be an option, although limited outcome data are available in support of this approach.

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younger patients alike, concerns regarding both toxicities and cost efficacy make its place in elderly breast cancer management uncertain. Increased comorbidities and polypharmacy are both more common in elderly patients. Additionally, physiological ageing can be associated with altered pharmacokinetics (drug absorption, distribution, metabolism and excretion). Each of these factors can affect the efficacy and toxicity of anti-cancer agents, making it critical that drug prescription in elderly patients be done with care. Eliminating or reducing the risk of drug interactions is best achieved with a thorough medication review before making any treatment decisions. Poor compliance or non-compliance with oral anti-cancer medications is not uncommon in older breast-cancer patients [3–5] and can lead to reduced efficacy of therapy. It is important to consider causes of non-compliance, which may often include poor tolerability of treatment. Thus, close adverseevent monitoring and addressing specific toxicity concerns and side-effects are crucial to improve compliance, treatment tolerability and efficacy. Older breast-cancer patients often rely more strongly on the recommendation of the cancer specialist regarding breast cancer management decisions; however, it is important to recognise that some older patients may wish to take a more active role in decision-making. While older patients are as likely to accept therapy as younger patients, they may be less willing to risk deterioration in quality of life for a potential improvement in survival [6]. For this reason, careful and clear discussions regarding diagnosis, prognosis and treatment options, as well as expectations of treatment and potential toxicities, are essential.

Conflict of interest statement 3.

Metastatic breast cancer None declared

• •

•

•

Chemotherapy is indicated for ER-negative, hormonerefractory, or rapidly progressing disease. Single-agent chemotherapy is generally preferred, although oral combination chemotherapy is also a reasonable option in elderly patients. There is no good evidence in support of routine dose or schedule modifications in elderly patients. However, this may be appropriate in certain circumstances, based on the known toxicities and pharmacology of the chemotherapy agents coupled with comorbidities in the patient. All patients with human epidermal growth factor receptor 2 (HER2) positive disease should be offered HER2-targeted therapy. In fit elderly patients, anti-HER2 therapy should be given in combination with chemotherapy. Anti-HER2 therapy plus endocrine therapy is a reasonable treatment option in patients with HER2-positive ER-positive disease in whom chemotherapy is contraindicated. Similarly patients with HER2-positive ER-negative disease who are not suitable for chemotherapy may be candidates for trastuzumab monotherapy. While bevacizumab has demonstrated benefit in terms of improved progression-free survival in both elderly and

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[1] National Cancer Institute Surveillance, Epidemiology and End Results. Breast cancer incidence and mortality. Available from: http://www.seer.cancer.gov/statfacts/html/breast.html. [2] Biganzoli L, Wildiers H, Oakman C, et al. Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol 2012;13:e148–60. [3] Partridge AH, Archer L, Kornblith AB, et al. Adherence and persistence with oral adjuvant chemotherapy in older women with early-stage breast cancer in CALGB 49907: adherence companion study 60104. J Clin Oncol 2010;28:2418–22. [4] Owusu C, Buist DS, Field TS, et al. Predictors of tamoxifen discontinuation among older women with estrogen receptorpositive breast cancer. J Clin Oncol 2008;26:549–55. [5] Crivellari D, Sun Z, Coates AS, et al. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol 2008;26:1972–9. [6] Crivellari D, Aapro M, Leonard R, et al. Breast cancer in the elderly. J Clin Oncol 2007;25:1882–90.

Mechanisms of treatment-related symptoms in cancer patients Charles S. Cleeland

*

The University of Texas MD Anderson Cancer Center, Department of Symptom Research, Houston, Texas, USA

Despite significant gains in our understanding of cancer biology, this progress has not matched what we know about the biology underlying the symptoms and toxic effects that therapies produce. These adverse symptoms can cause substantial discomfort, functional loss and distress to patients; they limit treatment tolerability, and can persist indefinitely in post-treatment survivorship [1]. Effective control of treatment-related symptoms could enhance therapeutic outcomes by improving patient health status, minimising toxicities that impair function, increasing adherence to curative treatments, maintaining health-related quality of life and potentially increasing survival. A mechanistic understanding of treatment-related symptoms would be of benefit in drug development, drug evaluation and early integration of appropriate supportive care in treatment planning. This presentation will present steps in a translational pathway for understanding and controlling treatment-related symptoms Cytotoxic therapies (chemotherapy, radiation) are expected to produce symptoms, because normal tissue and function are disrupted as cancer cells are killed. Targeted anticancer therapies were expected to destroy cancer cells specifically and therefore to cause less general toxicity, yet different and often severe toxicities have emerged, with each novel agent having its own unique toxicity profile

1. A translational pathway for treatmentrelated symptoms The difficulties inherent in translating laboratory findings into patient benefit are widely recognised in every disease area. In 2005, the National Cancer Institute created a Translational Research Working Group to speed the application of the findings of molecular oncology to patient care [2]. In response, the working group developed a model for a translational research pathway. Although the model was developed for new curative therapy, a similar model might be used to conceptualise how to move the collective basic and clinical symptom research into the clinic. A schematic illustrating such a trans-

lational pathway for symptom research is presented in Fig. 1, using fatigue as an example [3]. Early components of the pathway include discovery research steps and decision points based on longitudinal observational studies of patients, including patient interviews and determination of specific symptoms associated with disease, stage or treatment. Correlational studies showing the co-variation of biomarkers (such as inflammation) and symptom expression, although an important step, do not provide sufficient information on the mechanistic basis of symptom production for the development of potential agents targeted at symptom control. Instead, hypotheses about mechanisms underlying symptom expression are developed through examination of longitudinal symptom data, clinical correlates, biomarkers (genes, proteins) and brain imaging data obtained from patients. These hypothesised mechanisms are then tested in animal models. Candidate agents that may affect these mechanisms are developed in the laboratory, then applied in animal models of the specific disease. Agents that give some signal of effectiveness in preventing or reducing the specific cancer without excessive toxicity then move forward into patient research. For some symptoms, such as bone-related pain, sufficient progress has been made in animal models to provide a basic understanding of the mechanisms involved and to test agents that might have a clinical benefit. In contrast, much less is known about the development of animal models of such symptoms as treatment-related cognitive impairment, fatigue and treatment-related distress. Animal models of cognitive impairment and reduced motivation are available, but the effects on these models of having cancer and being treated for cancer have not been assessed. Biomedical research is largely dependent on having animal models of the targets of interest. The same applies to symptom science, where exploratory and confirmatory studies in humans can be conducted in parallel in animal models of symptom translational research in a bedside-to-bench and bench-to bedside collaboration. Fatigue research is an excel-

* Tel.: +1 713 745 3470; fax: +1 713 745 3593. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.063

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that modulate disease and those that modulate symptoms, to ensure that symptom control does not compromise curative benefit. Cancer-related symptoms are affected not only by treatment but also by individual host characteristics. There is substantial variation in the degree to which symptoms will impair patients, much like there is variance in the ability of a given drug to control cancer. Being able to predict this risk would benefit personalised cancer care. Potential predictors of high behavioural toxicity can be studied using advanced molecular genetic technologies. Analysis of genetic predictors for symptom occurrence and severity during treatment will help us to understand the biological basis of symptoms, identify susceptible individuals, develop tests with prognostic power, design novel drug targets and predict therapeutic outcomes. Finally, methods to reduce treatment-related symptoms will require early clinical investigation. Too many large-scale phase III symptom-focused clinical trials have been performed with negative results. Potential reasons for this include (a) lack of knowledge of the potential mechanisms producing the symptoms, (b) inadequate preclinical testing and (c) small early trials in patients to detect a signal. Just as with curative therapies, early use of adaptive clinical trial design could be employed to sort among agents that show promise for mitigating symptoms and to quickly cull those that do not [5].

Conflict of Interest statement None declared.

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Fig. 1 – Discovery and translational pathway for cancer symptom research.

lent example: many of the components of fatigue that patients describe—lack of motivation, increased cognitive problems and decreased motivation to be social—can be modelled in animals, and many are typical components of what is studied in animals as ‘sickness behaviour’ [4]. Animal models of disease and treatment-induced cancer pain have suggested both potential mechanisms of pain development and novel ways of treating cancer pain. Animal models also are necessary for preclinical testing of symptom agents. Generating hypotheses about symptom expression can lead to early phase trials in patients. Animal models that reflect symptomatic behaviours in a way that ‘makes sense’ to both patients and clinicians need to be developed on the basis of patient self-report of symptom severity and linked to animal behavioural, central nervous system (CNS) and systemic changes that reflect these symptoms. A critical step throughout the process is to determine the interaction between pathways

[1] Cleeland CS, Allen JD, Roberts SA, et al. Reducing the toxicity of cancer therapy: recognizing needs, taking action. Nat Rev Clin Oncol 2012;9:471–8. [2] Hawk ET, Matrisian LM, Nelson WG, et al. The translational research working group developmental pathways: introduction and overview; translational research working group. Clin Cancer Res 2008;14:5664–71. [3] Cleeland CS, Fisch MJ, Dunn AJ. Symptom research: looking ahead. In: Cleeland CS, Fisch MJ, Dunn AJ, editors. Cancer symptom science: measurement, mechanisms, and management. Cambridge UK: Cambridge University Press; 2011. p. 341–8. [4] Dantzer R, Meagher MW, Cleeland CS. Translational approaches to treatment-induced symptoms in cancer patients. Nat Rev Clin Oncol 2012;9:414–26. [5] Johnson VE, Mendoza TR. Bayesian adaptive design: a novel approach to test the effectiveness of symptom-reducing agents using patient-reported outcomes. In: Cleeland CS, Fisch MJ, Dunn AJ, editors. Cancer symptom science: measurement, mechanisms, and management. Cambridge UK: Cambridge University Press; 2011. p. 293–303.

Modern management of penile cancer V. Khoo

*

Royal Marsden NHS Foundation Trust and St. George’s NHS Trust, London, UK

1.

Introduction

Multidisciplinary management is the standard of care for common cancer subtypes, and it is particularly important for rare cancers such as penile cancer. Often clinical expertise may have to be concentrated into defined regional or supraregional cancer centres; thus patients may have to be treated at centres distant from their home town. For comprehensive management of the needs of penile patients, close communication is needed between the specialist cancer teams and local medical services, including community support services, particularly in the aftercare of surgery, for follow-up and in the palliative management of end-stage disease.

The major histopathological subtype is squamous-cell carcinoma (SCC), and this entity represents 95% of penile cancers. Other subtypes include melanoma and basal-cell carcinoma. Herein we will concentrate on malignant SCC of the penis. It has been reported that penile SCC may demonstrate four different patterns of growth [8] differing in natural history and prognosis [9]: superficial spreading, vertical growth, verrucous growth and multicentric growth. This will be relevant to surgical management to ensure that any surgical resection adequately encompasses the potential patterns of spread.

3. TNM (primary tumour, regional nodes and metastasis) classification 2. Background (epidemiology, incidence, path and biology) Penile cancer is relatively rare, representing about 0.5% of male cancers. It has an incidence in Western societies estimated at 1:100,000 [1]; a higher incidence is reported in non-Western societies such as South America, Africa (particularly Uganda) and Asia. Whilst it is more prevalent in older men, about 25% of cases are found in men younger than 40 years of age and about 10% in men under 30 years of age [2]. Predisposing factors include both cultural and religious practices as well as social and hygienic habits [3]. Of these, circumcision in newborns and before puberty, together with good hygiene, is associated with a reduced risk (by 3–4-fold) of penile cancer. Other risk factors include smoking [4], phimosis, inflammatory conditions such as lichen sclerosus or balanoposthitis, ultraviolet radiation [5] and the presence of human papilloma virus (HPV) that is related to sexual promiscuity. However, there is no clear evidence yet that the presence of HPV in penile cancer confers a worse prognosis [6], but rather that it may predict a favourable outcome [7].

The 2009 TNM classification listed in Table 1 has provided an update for the T1 category but still suffers from limitations in the T2 category, where corpus spongiosum involvement has been reported to be associated with a better prognosis than corpora cavernosa involvement [10]. Another limitation of the current TNM system is the lack of differentiation between T2 and T3 disease. One improvement is that the identification of retroperitoneal nodal disease is now accurately regarded as extra-regional disease or distant metastasis (M1).

4.

Prognostic factors

Early diagnosis and adequate staging is crucial to ensure that management is organised appropriately. Full examination of the penis and particularly of the surrounding nodal drainage regions is needed, as the primary drainage of the penis is into the inguinalnodes.Intheclinicallynegativeinguinaltheuseofultrasound may identify suspicious nodes suitable for fine-needle aspiration (FNA). Recent advances and improved techniques

* Address: Royal Marsden NHS Foundation Hospital, Fulham Road, Chelsea, London, SW3 6JJ, UK. Tel.: +44 20 7808 2911; fax: +44 20 7811 8017. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.059

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Table 1 – TNM classification of penile cancer. T T0 Tis Ta T1

Primary tumour No evidence of primary tumour Carcinoma in situ Non-invasive verrucous carcinoma, not associated with destructive invasion Tumour invades subepithelial connective tissue T1a Tumour invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated or undifferentiated (T1G1-2) T1b Tumour invades subepithelial connective tissue without with lymphovascular invasion or is poorly differentiated or undifferentiated (T1G3-4) T2* Tumour invades corpus spongiosum/corpora cavernosa T3 Tumour invades urethra T4 Tumour invades other adjacent structures N Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No palpable or visibly enlarged inguinal lymph node N1 Palpable mobile unilateral inguinal lymph node N2 Palpable mobile multiple or bilateral inguinal lymph nodes N3 Fixed inguinal nodal mass or pelvic lymphadenopathy, unilateral or bilateral M Distant metastases M0 No distant metastasis M1 Distant metastasis pN Regional lymph nodes pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node pN1 Intranodal metastasis in a single inguinal lymph node pN2 Metastasis in multiple or bilateral inguinal lymph nodes pN3 Metastasis in pelvic lymph node(s), unilateral or bilateral or extranodal extension of regional lymph node metastasis G Histopathological grading GX Grade of differentiation cannot be assessed G1 Well-differentiated G2 Moderately differentiated G3–4 Poorly differentiated/undifferentiated *

Ref. [20]

for sentinel-node biopsy have provided better identification of the relevant inguinal node(s) and have permitted extraction of the node for full histological evaluation compared with the limitations of using FNA.

5.

Clinical presentation and diagnosis

It is important to make a detailed examination of the penis with attention to the dimensions and location of the lesion and its relationship to the musculature of the penis. A deep biopsy is needed in equivocal cases, with dorsal slitting if there is a tight phimosis. Full assessment of the regional drainage regions, i.e., inguinal, is mandatory. If there are palpable nodes, then an FNA with or without ultrasound guidance should be undertaken. Further staging of the pelvis and abdomen will be needed using a computed tomography (CT) scan of the thorax, abdomen and pelvis. The role of magnetic resonance imaging (MRI) and positron emission tomography (PET) staging has not been fully established and remains under investigation. In clinical cases of negative inguinal nodes, where there is moderate to high risk of nodal involvement (PT1 G2), then dynamic sentinel node examination should be undertaken. The management schema described herein provides the policy guidelines followed within our supra-regional centre, one of the largest services within the United Kingdom.

6.

Management of primary disease

Ta lesions are treated conservatively, usually with circumcision for lesions located over the prepuce, whilst lesions on the glans can be treated using a wide local excision for smaller lesions, or for larger lesions a total glans resurfacing or glansectomy. T1 lesions of the prepuce are treated with circumcision, while lesions on the glans can be managed by either penispreserving surgery or radiotherapy. Penis-preserving surgery may utilise a wide local excision that may include skin grafting or glansectomy and skin grafting. Radiotherapy may be delivered using external-beam irradiation or brachytherapy which is the implantation of radioactive wires within the vicinity of the extent of the lesion. T2/T3 lesions of the penis can also be treated conservatively with surgery if there is only distal involvement of the glans and/or corporal heads, but frozen sections of the resection margins are needed to ensure adequacy of surgical clearance. The penis-preserving surgical methods include glansectomy and skin-graft reconstruction, or glansectomy and distal corporectomy and reconstruction. If clinically appropriate, penis preservation may also be considered for proximal lesions. In these cases, delayed reconstruction with a penile lengthening procedure may be considered. If penis preservation surgery is not possible, then another alternative

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is to use radiotherapy as described above, or radical penectomy with perineal urethrostomy. T4 lesions of the penis often require multimodal therapy for adequate local control. Down-staging with neo-adjuvant chemotherapy should be considered. The standard chemotherapy is usually a platinum-based regimen, often in combination 5-fluoro-uracil (5-FU) or capecitabine. The surgery is a penectomy with perineal urethrostomy. Alternatively, radiotherapy can be considered for local control in selected cases.

7.

Management of the regional nodes

7.1.

Clinically node negative at presentation

G1 Ta to T1 disease: in these cases, those patients with a negative ultrasound and FNA are at very low risk of nodal disease and they can safely be observed. G2 T1 lesions and above or T2 lesions G1-3: those patients with both a negative ultrasound FNA and dynamic sentinel node study are managed with surveillance. The surveillance programme involves clinical 2-monthly follow-up for the first year, 3-monthly follow-up for the second year and 4-monthly follow-up for the third year. During each follow-up visit, a full physical examination of the region is conducted, with ultrasound examination of the inguinal regions. A CT scan is undertaken only where there are specific clinical indications. For patients in whom the ultrasound FNA or dynamic sentinel node study is possible, then a modified radical inguinal node dissection will be performed on the ipsilateral side, with observation of the contralateral inguinal region. In these cases, all patients should have a staging CT scan of the thorax, abdomen and pelvis as a baseline, and this should be repeated every 6 months for 3 years.

7.2.

Clinically node positive at presentation

Those patients with clinically positive nodal disease should receive a modified radical inguinal-node dissection on the ipsilateral side and a dynamic sentinel-node study on the contralateral side. Baseline CT staging is also needed, with any other imaging based on clinical indications. Those patients who have been found to have extracapsular disease involvement should be offered postoperative radiotherapy to the ipsilateral region. For patients with multiple or bilateral superficial nodes, then bilateral inguinal-node dissection should be performed with consideration of pelvic nodal dissection. Postoperative radiotherapy should be offered in the presence of extracapsular disease involvement of the inguinal or pelvic nodal regions. Alternatively, if pelvic-node dissection cannot be undertaken, then external-beam radiotherapy can be used to cover the regions of risk together with the inguinal regions of extracapsular disease involvement. If there is large-volume pelvic disease then consideration should be directed towards combination therapy using chemo-radiation to the pelvis followed by consolidation chemotherapy or initial chemotherapy followed by chemoradiation to the pelvis. There are currently no evidence-based data on the most suitable management course or sequence of therapies in these cases.

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Chemotherapy for node-positive or high-risk disease is not given routinely. Where possible, recruitment into clinical trials of adjuvant therapy is strongly encouraged.

7.3.

Fixed or fungating inguinal nodes

In this situation, palliative inguinal-node dissection with appropriate covering flaps undertaken by a supporting plastic surgery team should be considered. External-beam radiotherapy may also be used postoperatively if there is extensive residual disease or as monotherapy for symptomatic palliative intent.

7.4.

Metastatic disease

The common sites of metastatic penile cancer disease are in the lungs, liver or nodal regions outside of the pelvis. The aim of palliative chemotherapy is to limit disease progression and to improve symptoms with the aim of maintaining a good quality of life for a good duration. Chemotherapy regimens are usually platinum-based (cisplatin or carboplatin, depending on renal clearance) in combination with either capecitabine or 5-fluorouracil. Other regimens include the combinations of carboplatin, methotrexate and bleomycin if fluoropyrimidines are contraindicated for cardiovascular disease. Alternatively taxane-containing regimens have been used. For localised metastatic lesions, palliative radiotherapy is effective in reducing painful symptoms.

8.

Palliative care

Palliative care is an important aspect of management that requires multidisciplinary input as outlined in the introduction. Integrated coordination between cancer teams and local support teams is vital and should be initiated early in the course of management.

9.

Conflict of interest statement

The author has disclosed no conflict of interest for this body of work. For further reading, please see references [11–19].

R E F E R E N C E S

[1] Barnholtz-Sloan JS, Maldonado JL, Pow-sang J, Giuliano AR. Incidence trends in primary malignant penile cancer. Urol Oncol 2007;25(5):361–7. [2] Burgers JK, Badalament RA, Drago JR. Penile cancer. Clinical presentation, diagnosis, and staging. Urol Clin North Am 1992;19(2):247–56. [3] Misra S, Chaturvedi A, Misra NC. Penile carcinoma: a challenge for the developing world. Lancet Oncol 2004;5(4):240–7. [4] Hellberg D, Valentin J, Eklund T, Nilsson S. Penile cancer: is there an epidemiological role for smoking and sexual behaviour? Br Med J (Clin Res Ed) 1987; 21:295(6609): 1306–8.

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[5] Stern RS. Genital tumors among men with psoriasis exposed to psoralens and ultraviolet A radiation (PUVA) and ultraviolet B radiation. The photochemotherapy follow-up study. N Engl J Med 1990;322(16):1093–7 [19]. [6] Bezerra AL, Lopes A, Santiago GH, Ribeiro KC, Latorre MR, Villa LL. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer 2001;91(12):2315–21 [15]. [7] Lont AP, Kroon BK, Horenblas S, et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer 2006;119(5):1078–81. [8] Cubilla AL, Barreto J, Caballero C, Ayala G, Riveros M. Pathologic features of epidermoid carcinoma of the penis. A prospective study of 66 cases. Am J Surg Pathol 1993;17(8):753–63. [9] Villavicencio H, Rubio-Briones J, Regalado R, et al. Grade, local stage and growth pattern as prognostic factors in carcinoma of the penis. Eur Urol 1997;32(4):442–7. [10] Leijte JA, Gallee M, Antonini N, Horenblas S. Evaluation of current TNM classification of penile carcinoma. J Urol 2008;180(3):933–8 [discussion 8]. [11] Pizzocaro G, Algaba F, Horenblas S, et al. EAU penile cancer guidelines 2009. Eur Urol 2010;57(6):1002–12. [12] Maclennan SJ, Imamura M, Omar MI, et al. Urological cancer care pathways: development and use in the context of systematic reviews and clinical practice guidelines. World J Urol 2011;29(3):291–301.

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[13] Leijte JA, Hughes B, Graafland NM, et al. Two-center evaluation of dynamic sentinel node biopsy for squamous cell carcinoma of the penis. J Clin Oncol 2009;27(20):3325–9. [14] Graafland NM, Lam W, Leijte JA, et al. Prognostic factors for occult inguinal lymph node involvement in penile carcinoma and assessment of the high-risk EAU subgroup: a twoinstitution analysis of 342 clinically node-negative patients. Eur Urol 2010;58(5):742–7. [15] Lam W, Alnajjar HM, La-Touche S, et al. Dynamic sentinel lymph node biopsy in patients with invasive squamous cell carcinoma of the penis: a prospective study of the long-term outcome of 500 inguinal basins assessed at a single institution. Eur Urol 2013;63(4):657–63. [16] Hegarty PK, Shabbir M, Hughes B, et al. Penile preserving surgery and surgical strategies to maximize penile form and function in penile cancer: recommendations from the United Kingdom experience. World J Urol 2009;27(2):179–87. [17] Crook J. Radiation therapy for cancer of the penis. Urol Clin North Am 2010;37(3):435–43. [18] de Crevoisier R, Slimane K, Sanfilippo N, et al. Long-term results of brachytherapy for carcinoma of the penis confined to the glans (N- or NX). Int J Radiat Oncol Biol Phys 2009;74(4):1150–6. [19] Pagliaro LC, Crook J. Multimodality therapy in penile cancer: when and which treatments? World J Urol 2009;27(2):221–5. [20] Sobin LH, Gospodariwics M, Wittekind C (Eds). In: TNM classification of malignant tumors. UICC International Union Against Cancer 7th ed., Wiley-Blackwell, 2009, pp. 239–42.

Practical tips and tricks with recently approved molecular targeted agents in non-small-cell lung cancer Stefan Zimmermann, Solange Peters

*

Centre Hospitalier Universitaire Vaudois (CHUV), Oncology Department, Lausanne, Switzerland

The detection of driver mutations in the epidermal growth factor receptor (EGFR), the rearrangement of anaplastic lymphoma kinase (ALK) genes and the subsequent development of targeted therapy have transformed the treatment of lung cancer. In a Caucasian population, as illustrated by the Biomarker France database, these alterations represent 9.4% and 4.0%, respectively, in 10,000 samples of non-small-cell lung cancer (NSCLC) [1]. Of these patients, 56.9% received treatment according to their molecular profile, either with labelled drugs or in a bio-guided trial. Similarly, the Lung Cancer Mutation Consortium, after testing more than 1000 patients with lung adenocarcinoma, found 15% to harbour an EGFR mutation and 8% an ALK rearrangement [2]. An actionable driver alteration was detected in 62% of these tumours. The use of targeted therapies has raised practical questions related to therapy sequences and durations, the role of chemotherapy, the role of combination with chemotherapy, the validity of Response Evaluation Criteria in Solid Tumours (RECIST) criteria, utility of therapeutic rechallenge with the same drugs and several additional issues that arise in the wake of all significant medical progress. This article will address some of these questions and highlight some areas of controversy.

2.

Whom and when to test?

The College of American Pathologists recommends testing for EGFR mutations and ALK rearrangements in all patients with lung adenocarcinoma, irrespective of clinical characteristics. In the setting of lung cancer resection specimen availability, EGFR and ALK testing is recommended for adenocarcinomas and mixed lung cancers with an adenocarcinoma component, but is not recommended in lung cancer that lacks any adenocarcinoma component. In the setting of more limited lung cancer specimens (biopsy, cytology) where an adenocarcinoma component cannot be excluded, EGFR and ALK testing may be performed in cases showing squamous- or small-cell

histology, with clinical criteria such as young age and lack of smoking history being useful in selecting the subset for testing. Primary tumours or metastatic lesions are considered equally suitable for testing, and testing of many different areas within a single tumour is not necessary. For patients with multiple, apparently separate, primary lung adenocarcinomas, each tumour should be evaluated. Testing should be ordered at the time of initial diagnosis of advanced-stage disease (stage IV according to the tumour-node-metastasis (TNM) staging system 7th edition) or at the time of recurrence or progression in patients who originally presented with lower-stage disease. Testing for EGFR should be prioritised over other molecular markers, followed by ALK, and only later other molecular markers in lung adenocarcinoma, for which published evidence is insufficient to support the development of testing guidelines at the present time [3].

3.

When to start treatment?

First-line EGFR tyrosine kinase (TKI) therapy in patients whose tumour harbours an activating mutation of the EGFR gene has not translated into prolonged overall survival in four randomised trials with mature overall survival (OS) data [4–7], owing to the fact that the vast majority of patients receiving chemotherapy as first-line treatment received EGFR TKI as salvage therapy upon disease progression [4–9]. Why do guidelines advocate use of first-line over chemotherapy [10]? To start with, EGFR mutational status may be altered under first-line chemotherapy, and selection of patients for targeted therapy on the basis of molecular testing on the initial biopsy may be inadequate [11]. Furthermore, in the randomised trials, up to 41% of patients treated with initial chemotherapy did not receive second-line EGFR TKI, mostly because of rapid tumour progression leading to death or reduced performance status, thus excluding these patients form the opportunity to receive the most efficient treatment [5–7]. Quality-of-life data also favour use of EGFR TKI over

* Corresponding author: Tel.: +41 795560192. E-mail address: [email protected] (S. Peters). 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.058

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chemotherapy in first-line treatment. Finally, the high intracranial response rate of EGFR TKIs may defer use of cerebral radiotherapy in patients with central nervous system metastatic disease. ALK TKIs such as crizotinib are being studied for first-line treatment. Their use is restricted to second and further lines at the present time. OS has not been reported, and is unlikely to be improved as the study design allowed for cross-over to crizotinib in the control arms upon disease progression.

4.

Which TKI to choose?

Gefitinib, erlotinib and afatinib have shown significant prolongation of progression-free survival (PFS) in the first-line setting as compared with a platinum doublet. No adequately powered trial has compared these TKIs. Gefitinib and erlotinib are both appropriate as first-line treatment, afatinib being commercially unavailable at the present time with a possible slightly higher gastrointestinal toxicity.

5.

When to stop treatment?

All patients on EGFR TKI ultimately develop acquired resistance, which translates into progressive disease as per RECIST criteria. However, only a fraction of tumour clones might carry a resistance mechanism, and interruption of TKI therapy may result in tumour flares. The ASPIRATION trial (NCT01310036) currently compares PFS evaluated by RECIST criteria with PFS until ‘progressive disease according to the investigator’, defined as symptomatic progression, multiple progression or threat to a major organ. A randomised phase II trial compared chemotherapy plus erlotinib with chemotherapy alone in EGFR TKI-responsive NSCLC that subsequently progresses [12]. No improvement in PFS or OS could be detected, although the number of enrolled patients was low and the trial terminated early. Improvement in RR but not in PFS or OS could be shown in a recent retrospective trial [13]. However, the controversy about continuing EGFR TKI beyond progression is ongoing, with promising retrospective results reported against the switch to chemotherapy [14,15] or by adding local treatment to TKI [16], or combining TKI with chemotherapy [17]. The IMPRESS trial is an ongoing phase III trial expected to clarify the role of TKIs beyond progression. For progression limited to the brain, local therapy to the area of progression may lead to prolonged disease control.

6.

What to do upon disease progression?

Despite initial activity of EGFR TKIs, all patients eventually develop acquired resistance. The most common mechanism of resistance is the EGFR T790M secondary mutation, which accounts for 50–60% of cases, and results in increased kinase affinity for adenosine triphosphate [18]. Second-generation EGFR TKIs – such as neratinib, afatinib and dacomitinib – are effective in preclinical gefitinib- and erlotinib-resistant EGFR T790M models, but to date their delivery in EGFR TKIresistant patients have shown disappointing results in the clinic. Combination of afatinib with cetuximab in EGFR TKIresistant patients resulted in a 30% response rate and 75%

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disease control rate, with significant gastrointestinal toxicity [19]. Other mechanisms of resistance include MET amplification, with no commercially available inhibitor, HER2 amplification potentially amenable to treatment with anti-HER2 monoclonal antibodies or histological transformation to small-cell lung cancer, which requires cytotoxic chemotherapy. Additional potential mechanisms of acquired resistance to EGFR TKIs may develop, including altered EGFR trafficking, amplification or activation of downstream or overlapping pathways and expression of drug-efflux transporters. Standard treatment upon progression on EGFR TKI remains cytotoxic chemotherapy. Later rechallenge with EGFR TKI may result in some modest degree of response (range 4–24%) and a significant disease control rate (range 45–67%) [20–22]. Resistance mechanisms to crizotinib are multiple, and include ALK-dominant mechanisms such as resistance mutations and copy number gain, and ALK non-dominant mechanisms through the outgrowth of clones containing a separate activated oncogene. In contrast to the EGFR setting, where the T790M mutation predominates, the spectrum of ALK resistance mutations is broad. Several distinct secondgeneration ALK inhibitors which are potentially efficient in preventing/overcoming TKI resistance are under development. A response rate of 80% has been observed during treatment with LDK378 in patients who had experienced disease progression after crizotinib treatment [23]. Similarly to EGFR TKIs, successful later rechallenge with ALK inhibitors has been reported in case reports [24].

7.

What toxicity to expect?

Grade 3 or 4 toxicities occur infrequently with EGFR TKIs, with the exception of skin rash, fatigue and diarrhoea (13%, 6% and 5%, respectively in the Caucasian European Randomised Trial of Tarceva versus Chemotherapy (EURTAC) cohort). Grade 1 or 2 toxicities, however, occur in most patients, with rash, fatigue and diarrhoea bothering the majority of patients (67%, 51% and 52%, respectively), and with appetite loss, alopecia, anaemia and arthralgia occurring in a minority of patients (31%, 14%, 11% and 10%, respectively). Rare but potentially fatal interstitial pneumonitis occurs in 1% of patients. Overall, one third of patients require dose reduction or treatment discontinuation because of adverse effects [9]. Topical skin care is mandatory. Systemic antibiotics and anti-diarrhoeal drugs may be necessary to manage higher-grade toxicity. Frequent toxicities of the ALK inhibitor crizotinib include vision disorders (62%), nausea (53%) and diarrhoea (43%). Patients are less frequently affected by oedema (28%), constipation (27%), fatigue (20%) decreased appetite (19%), dizziness (16%) and dysgeusia (12%). Potentially dose-limiting, increased alanine aminotransferase levels occur in 13% of patients, with less than 5% being of grade 3 or 4. Rapid-onset low testosterone is common in male patients. Renal cysts and pneumonitis have been described, but their frequency is unknown [25,26].

Conflict of interest statement None declared.

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[13] [1] Barlesi F, Blons H, Beau-Faller M, et al. Biomarkers (BM) France: results of routine EGFR, HER2, KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 10,000 non-small cell lung cancer (NSCLC) patients (pts). J Clin Oncol 2013;31:abstr 8000. [2] Johnson EB, Kris MG, Berry LD, et al. A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 2013;31:abstr 8019. [3] Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013;8:823–59. http://dx.doi.org/10.1097/ JTO.0b013e318290868f. [4] Han JY, Park K, Kim SW, et al. First-SIGNAL: first-line singleagent iressa versus gemcitabine and cisplatin trial in neversmokers with adenocarcinoma of the lung. J Clin Oncol 2012;30:1122–8. [5] Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121–8. [6] Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–57. [7] Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735–42. [8] Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380–8. [9] Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-smallcell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239–46. [10] Peters S, Adjei AA, Gridelli C, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23(Suppl. 7):vii56–>vii64. [11] Bai H, Wang Z, Chen K, et al. Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer. J Clin Oncol 2012;30:3077–83. [12] Halmos B, Pennell NA, Otterson GA, et al. Erlotinib beyond progression study: randomized phase II study comparing chemotherapy plus erlotinib with chemotherapy alone in EGFR tyrosine kinase inhibitor (TKI)-responsive, non-small

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cell lung cancer (NSCLC) that subsequently progresses. J Clin Oncol 2013;31:abstr 8114. Goldberg SB, Oxnard GR, Digumarthy S, et al. Chemotherapy with erlotinib or chemotherapy alone in advanced NSCLC with acquired resistance to EGFR tyrosine kinase inhibitors (TKI). J Clin Oncol 2012;30:abstr 7524. Nishie K, Kawaguchi T, Tamiya A, et al. Epidermal growth factor receptor tyrosine kinase inhibitors beyond progressive disease: a retrospective analysis for Japanese patients with activating EGFR mutations. J Thorac Oncol 2012;7:1722–7. Yang JJ, Chen HJ, Yan HH, et al. Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer. Lung Cancer 2013;79:33–9. Oxnard GR, Lo P, Jackman DM, et al. Delay of chemotherapy through use of post-progression erlotinib in patients with EGFR-mutant lung cancer. J Clin Oncol 2012;30:abstr 7547. Faehling M, Eckert R, Kamp T, et al. EGFR-tyrosine kinase inhibitor treatment beyond progression in long-term Caucasian responders to erlotinib in advanced non-small cell lung cancer: a case–control study of overall survival. Lung Cancer 2013;80:306–12. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240–7. Janjigian JJ et al. Activity of afatinib/cetuximab in patients with EGFR mutant NSCLC and acquired resistance to EGFR inhibitors. Ann Oncol 2012;23. abstr 12270. Tomizawa Y, Fujita Y, Tamura A, et al. Effect of gefitinib rechallenge to initial gefitinib responder with non-small cell lung cancer followed by chemotherapy. Lung Cancer 2010;68:269–72. Koizumi T, Agatsuma T, Ikegami K, et al. Prospective study of gefitinib readministration after chemotherapy in patients with advanced non-small-cell lung cancer who previously responded to gefitinib. Clin Lung Cancer 2012;13:458–63. Heon S, Nishino M, Goldberg SB, et al. Response to EGFR tyrosine kinase inhibitor (TKI) retreatment after a drug-free interval in EGFR-mutant advanced non-small cell lung cancer (NSCLC) with acquired resistance. J Clin Oncol 2012;30:abstr 7525. Shaw AT, Camidge DR, Felip E, et al. Results of a first-inhuman phase I study of the ALK inhibitor LDK378 in advanced solid tumours. Ann Oncol 2012;23:abstr 4400. Browning ET, Weickhardt AJ, Camidge DR. Response to crizotinib rechallenge after initial progression and intervening chemotherapy in ALK lung cancer. J Thorac Oncol 2013;8:e21. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693–703. Shaw AT, Kim D-W, Nakagawa K, et al. Phase III study of crizotinib versus pemetrexed or docetaxel in patients with advanced ALK-positive NSCLC (PROFILE 1007). Ann Oncol 2012;23. abstr LBA1 PR.

Role of expert centres in the management of sarcomas Ian Judson

*

Royal Marsden Hospital, Sutton UK

1.

Introduction

Sarcomas are rare tumours of the connective tissue which may resemble a variety of tissues – such as muscle, nerve and bone – although many sarcomas have no normal tissue counterpart. The annual incidence of soft-tissue sarcomas (STSs) in England and Wales between 1990 and 2007 was 2300, which equates to about 40 per million per annum. Bone sarcomas are significantly less common, representing only 0.2% of all malignancies. Treatment within specialised multidisciplinary teams (MDTs) is crucial since a body of expertise in all areas of diagnosis and treatment is required to manage them appropriately. Studies have shown that conformity to approved treatment guidelines is improved when patients are treated by an MDT in a reference centre [1].

2.

Diagnosis – histopathology, radiology

The risk of a tumour being metastatic at diagnosis, and of subsequent death, is directly related to tumour size [2]. Earlier diagnosis could have a huge impact, and guidelines are now in place in the UK to encourage early referral of suspicious lumps (or X-rays in the case of bone tumours). Once a tumour is suspected, the two key diagnostic tools are radiology and histopathology. The initial assessment of suspicious lumps will be by physical examination and probably ultrasound, followed by core needle biopsy. Core needle biopsy has an accuracy of >90% as well as the ability to distinguish high-grade from lowgrade lesions and in most cases the specific sarcoma subtype [3]. Cross-sectional imaging is required prior to surgery, in order to plan treatment and for staging. This is usually in the form of magnetic resonance imaging (MRI) for the primary disease site and computed tomography (CT) for staging purposes. It is common

for the diagnosis of patients referred with a diagnosis of sarcoma to be revised to another subtype, another disease, or even a benign condition [4]. Reported discrepancy rates between referring and expert pathologists are generally in the order of 25%, with a benign to malignant discrepancy of 5%.

3.

Sarcoma surgery

The primary management of most sarcomas is surgical excision. Unplanned operations, performed on the assumption that the ‘‘lump’’ is benign, can make the eradication of disease much more difficult. A study demonstrated that patients who had unplanned surgery had a much higher local recurrence rate and poorer longterm disease control, in spite of definitive surgery and radiotherapy [5]. All sarcoma operations should be performed in specialised centres in order to ensure optimum outcomes. For retroperitoneal surgery, where multivisceral resections are common, guidance is available [6]. The NICE (National Institute for Health and Care Excellence) Improving Outcomes Guidance (IOG) for people with sarcoma recommended that specialised centres should treat a minimum of 100 STS a year and 50 in the case of bone sarcomas. The IOG, which also addresses wider issues concerning the sarcoma MDT, can be obtained using the following URL: http://guidance.nice.org.uk/CSG

4.

Radiation oncology

Adjuvant radiotherapy improves the local control of highgrade extremity soft tissue sarcomas [7]. Research continues into the appropriate timing, dose and field size of adjuvant irradiation. The complexity of pre- and post-operative radiotherapy for sarcomas is such that specialised centres are best placed to offer the appropriate expertise, in the context of the MDT.

* Tel.: +44 208 722 4303; fax: +44 208 642 7979. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.061

EJC SUPPLEMENTS

5.

Medical oncology

Chemotherapy for most sarcomas is palliative, but nevertheless valuable. Recent years have seen a significant increase in treatment options and tailoring of treatment to the individual disease subtype. The standard agents, doxorubicin and ifosfamide, remain useful, but other drugs are now in routine use, including gemcitabine plus docetaxel for leiomyosarcoma and pleomorphic sarcoma [8,9], trabectedin for leiomyosarcoma and liposarcoma [10] and paclitaxel for angiosarcoma [11]. The management of gastrointestinal stromal tumour (GIST) was transformed by the introduction of imatinib [12,13], and subsequently sunitinib [14]. More recently another tyrosine kinase inhibitor, pazopanib, has been licensed for treatment of STS [15]. Certain rarer diseases require special approaches: e.g. the use of rapamycin analogues for PEComa, imatinib for chordoma, tamoxifen for fibromatosis and aromatase inhibitors for endometrial stromal sarcoma.

6.

Clinical trials and data collection

Clearly, for such a rare group of diseases it is essential that care be concentrated in specialised centres which can treat patients in appropriate clinical trials. These will not be available in smaller centres, putting patients at a disadvantage. The cumulative experience of the MDT together with the amalgamation of clinical and laboratory data also represent a major resource for research and the opportunity to use these data directly for the benefit of patients.

7.

The wider multidisciplinary team

In addition to surgeons, radiation and medical oncologists, radiologists and histopathologists, the MDT will have clinical nurse specialists, physiotherapists, dieticians, palliative care physicians and site-specific specialists. As described, the management of sarcomas is truly multidisciplinary, increasingly complex and, as more molecular targets are identified, more likely to be treated with highly specific targeted therapy. The need for specialised centres has been recognised in the UK, and a process, informed by the NICE IOG, is leading to the concentration of care in a limited number of centres. We hope that earlier diagnosis, fewer unplanned operations and better integrated care will lead to a significant improvement in outcomes, which have not changed over the last 20 years (http://www.ncin.org.uk/publications/data_briefings/soft_tissue_sarcoma). We can only hope to do better.

Conflict of interest statement None declared.

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R E F E R E N C E S

[1] Ray-Coquard I, Thiesse P, Ranchere-Vince D, et al. Conformity to clinical practice guidelines, multidisciplinary management and outcome of treatment for soft tissue sarcomas. Ann Oncol 2004;15:307–15. [2] Grimer RJ. Size matters for sarcomas! Ann R Coll Surg Engl 2006;88:519–24. [3] Strauss DC, Qureshi YA, Hayes AJ, Thway K, Fisher C, Thomas JM. The role of core needle biopsy in the diagnosis of suspected soft tissue tumours. J Surg Oncol 2010;102:523–9. [4] Thway K, Fisher C. Histopathological diagnostic discrepancies in soft tissue tumours referred to a specialist centre. Sarcoma 2009;2009:7. http://dx.doi.org/10.1155/2009/ 741975 [Article ID 741975]. [5] Qureshi YA, Huddy JR, Miller JD, Strauss DC, Thomas JM, Hayes AJ. Unplanned excision of soft tissue sarcoma results in increased rates of local recurrence despite full further oncological treatment. Ann Surg Oncol 2012;19:871–7. [6] Bonvalot S, Raut CP, Pollock RE, et al. Technical considerations in surgery for retroperitoneal sarcomas: position paper from E-Surge, a master class in sarcoma surgery, and EORTC-STBSG. Ann Surg Oncol 2012;19:2981–91. [7] Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859–68. [8] Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 2002;20:2824–31. [9] Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol 2007;25:2755–63. [10] Demetri GD, Chawla SP, von Mehren M, et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol 2009;27:4188–96. [11] Schlemmer M, Reichardt P, Verweij J, et al. Paclitaxel in patients with advanced angiosarcomas of soft tissue: a retrospective study of the EORTC soft tissue and bone sarcoma group. Eur J Cancer 2008;44:2433–6. [12] Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–80. [13] Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004;364:1127–34. [14] Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329–38. [15] van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012;379:1879–86.

Therapeutic procedures in liver metastases: Conventional and future measures Laura A. Dawson

*

University of Toronto, Department of Radiation Oncology, Princess Margaret Cancer Centre, Radiation Medicine Program, Toronto, Canada

1.

Background

Resection of liver metastases from colorectal carcinoma (CRC) is associated with 5-year survival rates of 30–40%, with the possibility of cure, even in the absence of systemic therapy. This demonstration of a local therapy improving outcomes for ‘oligo-metastatic’ CRC is well accepted. Long-term survivors have also been reported following resection of liver metastases from sarcoma, renal-cell carcinoma, breast cancer and melanoma, with 5-year survival rates of 23–36% in a series of non-CRC liver metastases. Resection of neuroendocrine liver metastases has also been associated with favourable survival. Stereotactic body radiation therapy (SBRT) is an attractive option for patients with liver metastases. Liver SBRT requires a planning computed tomography (CT) simulation scan with intravenous (IV) contrast for target definition. Multimodal imaging with contrast-enhanced magnetic resonance imaging (MRI) or positron emission tomography (PET) may improve target delineation. Breathing-related liver motion should be assessed by respiratory-correlated (or 4D) CT, cine-MRI or 2D kV fluoroscopy to determine appropriate planning target volume (PTV) margins. Highly conformal dose distributions are desirable using multiple beams or arcs in coplanar or non-coplanar geometries. The nominal prescribed dose should reflect the isodose that encompasses the PTV (or 95% of the PTV) with hotspots within the PTV. Immobilization of the liver using controlled breath holds, shallow breathing, abdominal compression and gating of the RT (radiation therapy) beam during specified phases of the respiratory cycle, medications and tumour tracking of implanted fiducial markers may help reduce the adverse effects of breathing motion. Image-guided RT (IGRT) based on orthogonal imaging, ultrasound or volumetric imaging such as MV or kV cone beam CT, is required at every fraction in order to reduce PTV margins for setup uncertainty. MR IGRT is an area of active research that may benefit patients requiring liver SBRT.

Advantages of SBRT include increased convenience for patients. Furthermore, there are preclinical data demonstrating dose-per-fraction effects (e.g. endothelial and immune effects), with a threshold of approximately 8 Gray (Gy). Clinical experience in SBRT for liver metastases is rapidly increasing.

2.

Methods

Updated results from Princess Margaret Cancer Centre phase I/II studies of SBRT for liver metastases are presented, as well as a review of previously published SBRT studies and consensus statements of radiation therapy for liver metastases.

3.

Results

In our centre in Toronto, a phase I/II study of individualised IGRT-guided SBRT was conducted in 107 patients with 172 unresectable or medically inoperable liver metastases from CRC, breast cancer or other primary sites [1]. The median tumour volume was 75 ml. Extrahepatic disease was present in 40 patients (43%), and 75% had received prior systemic therapy. Patients were treated with six-fraction SBRT (median dose 42 Gy, range 24–48 Gy). No radiation-induced liver toxicity was observed. Median survival was 18.1 months. The presence of extrahepatic disease was associated with worse survival. Prognostic factors for improved local control included breast primary site, dose and tumour volume. Some patients with CRC or breast cancer liver metastases are alive with no progressive disease more than 5 years post-SBRT. In a subset of patients from the Toronto cohort with unresectable liver metastases who had kV cone-beam CT scans at each fraction, the cone-beam CTs were used in combination with deformable image registration to deter-

* Tel.: +1 416 946 2125; fax: +1 416 946 6566. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.060

EJC SUPPLEMENTS

mine the accumulated delivered dose (versus the prescribed dose). Accumulated minimum doses to the GTV (gross tumour volume) of 45 Gy, in six fractions were associated with 18-month local control of 33%, 55% and 83%, respectively. The dose–response relationship was steeper for accumulated dose compared with prescribed dose. Most published SBRT studies have prescribed doses in the range 30–60 Gy in 1–6 fractions, for 700 ml receiving 15 Gy in three fractions or mean liver dose 42 Gy in three fractions are used. Local control is also improved in patients with metastases